Tricyclic prostaglandin intermediates

ABSTRACT

Process for preparing bicyclic diols of the formula ##STR1## wherein C p  H 2p  is a valence bond or alkylene of one to 4 carbon atoms, inclusive, with one or 2 carbon atoms in the chain between the phenylene ring and --O--; wherein Y is a hydrocarbyl or substituted hydrocarbly group; and wherein   indicates attachment to the cyclopropane ring in exo or endo configuration. These diols and the intermediates prepared herein are useful intermediates in preparing prostaglandin analogs having pharmacological utility.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division, of application Ser. No. 604,159, filed Aug. 13, 1975now U.S. Pat. No. 3,997,566, which is a continuation-in-part ofcopending application Ser. No. 552,707 filed Feb. 24, 1975, nowabandoned, which was a continuation-in-part of co-pending applicationSer. No. 488,295 filed July 12, 1974, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to intermediates useful in the preparation ofprostaglandin analogs and to a process for preparing them.

Each of the known prostaglandins is a derivative of prostanoic acidwhich has the following structure and atom numbering: ##STR2## Asystematic name for prostanoic acid is7-[(2β-octyl)-cyclopent-1α-yl]heptanoic acid.

Prostaglandin E₁, "PGE₁ ", has the following structure: ##STR3##

Prostaglandin F₁α, "PGF₁α ", has the following structure: ##STR4##

The prostaglandin formulas mentioned above each have several centers ofasymmetry. Each formula represents a molecule of the particularoptically active form of the prostaglandin obtained from certainmammalian tissues, for example, sheep vesicular glands, swine lung, andhuman seminal plasma, or by reduction or dehydration of a prostaglandinso obtained. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1(1968), and references cited therein. The mirror image of each formularepresents a molecule of the other enantiomeric form of thatprostaglandin. The racemic form of the prostaglandins consists of equalnumbers of two types of molecules, one represented by one of the aboveformulas and the other represented by the mirror image of that formula.Thus, both formulas are needed to define a racemic prostaglandin. SeeNature 212, 38 (1966) for discussion of the stereochemistry of theprostaglandins.

In the formulas above, as well as in the formulas given hereinafter,broken line attachments to the cyclopentane ring indicate substituentsin alpha configuration, i.e., below the plane of the cyclopentane ring.Heavy solid line attachments to the cyclopentane ring indicatesubstituents in beta configuration, e.e., above the plane of thecyclopentane ring. In the formulas above, the hydroxyl attachment tocarbon 15 is in the alpha configuration, as indicated by the brokenline. In formulas below, this convention is also used for intermediateshaving hydroxyl substituted at the corresponding position on the sidechain. A wavy line indicates attachment to the side chain in alpha orbeta configuration.

The various optically active and racemic prostaglandins and their alkylesters are useful for various pharmacological purposes. With particularregard to PGF₁α see, for example, Bergstrom et al., Pharmacol. Rev. 20,1 (1968), and references cited therein. As to the other prostaglandins,see. for example, Ramwell et al., Nature 221, 1251 (1969).

Previously, certain prostaglandin analogs having an oxa oxygen (--O--)and a divalent phenylene moiety ##STR5## in the carboxyl-terminated sidechain of the prostanoic acid structure (l) were disclosed. See GermanOffelegungsschrift No. 2,209,990, Derwent Farmdoc No. 66750T.

Included among those phenylene-oxa prostaglandin analogs were compoundsrepresented by the formulas:

    ______________________________________                                        IV                                                                             ##STR6##                                                                      ##STR7##                                                                     VI                                                                             ##STR8##                                                                     VII                                                                            ##STR9##                                                                     VIII                                                                           ##STR10##                                                                    IX                                                                             ##STR11##                                                                    X                                                                              ##STR12##                                                                    XI                                                                             ##STR13##                                                                    ______________________________________                                    

and the racemic mixtures of those compounds and their respectiveenantiomers represented by the mirror images of the above formulas. Theterms C_(p) H_(2p), C_(t) H_(2t), R₁, R₂, and R₃, T, and s will bedefined and illustrated below.

For example, specific compounds among the above phenylene-oxaprostaglandin analogs are represented by the following formulas by wayof illustration:

    ______________________________________                                                                      XII                                              ##STR14##                                                                                                  XIII                                             ##STR15##                                                                                                  XIV                                              ##STR16##                                                                    ______________________________________                                         based on its relationship to PGE.sub.1 and prostanoic acid, the compound     of formula XII is named 3-oxa-4,7-inter-m-phenylene-5,6-dinor-PGE.sub.1.     Similarly, the compound of formula XIII is named     3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF.sub.1α. methyl ester     and the compound of formula XIV is named     3-oxa-3,7-inter-p-phenylene-15(R)-15-methyl-17-phenyl-4,5,6,18,19,20-hexan    or-PGF.sub.1.

These names for the compounds of formulas XII, XIII, and XIV are typicalof the names of the phenylene-oxa prostaglandin analogs produced by theintermediates obtained by the novel process herein. These names arebased on the structure and numbering system of prostanoic acid (formulaI, above). That formula has seven carbon atoms in the carboxy-terminatedchain and eight carbon atoms in the hydroxy-containing chain. In thesenames. "3-oxa" indicates an oxa oxygen (--O--) in place of the C-3methylene of the prostaglandin (PG) compound.

The use of "nor", "dinor", "trinor", "tetranor", "pentanor", "hexanor",and the like in the names for the PG analogs referred to hereinindicates the absence of one or more of the chain carbon atoms and theattached hydrogen atoms. The number or numbers preceding nor, dinor,etc., indicate which of the orginal prostanoic acid carbon atoms aremissing in the named compound.

Each of the names of the PG analogs referred to herein contains(inter-p-phenylene). (inter-m-phenylene), or (inter-o-phenylene),preceded by two numbers. That indicates that p-phenylene, m-phenylene,or o-phenylene has been inserted between (inter) the two carbon atoms sonumbered in the formula of prostanoic acid.

Thus, formula XII differs from PGE₁ and prostanoic acid in that an oxaoxygen replaces carbon 3, carbons 5 and 6 are missing, and m-phenyleneis inserted between carbons 4 and 7.

Included in the above analogs are those with epi configuration for thehydroxy at C-15, illustrated by formula XIV. Where the C-15configuration is the same as that of the natural prostaglandin PGE₁,identified as "S" configuration, the name ordinarily does not identifythe configuration at C-15 unless there is 15-alkyl substitution. If the15-epimer is intended, the name usually includes "15(R)" or "15-beta".See R. S. Cahn, Journal of Chemical Education 41, 116 (1964) for adiscussion of S and R configurations.

Formulas IV, VI, VIII, and X as printed represent optically activeprostaglandin analogs with the same absolute configuration as PGE₁ orPGF₁α obtained from mammalian tissues. Formulas V, VII, IX, and XIrepresent their respective 15-epimers. Each of formulas IV-XI plus itsmirror image describes a racemic mixture designated herein by the prefix"racemic" or "dl" before its name. When that prefix is absent, theintent is to designate an optically active compound represented by theappropriate formula.

In formulas IV-XI and wherever used in this disclosure, the term C_(n)H_(2n) represents alkylene of one to 4 carbon atoms, inclusive; C_(p)H_(2p) represents a valence bond or alkylene of one to 4 carbon atoms,inclusive, with one or 2 carbon atoms in the chain between the phenylring and --C--. C_(t) H_(2t) represents a valence bond or alkylene ofone to 10 carbon atoms, inclusive, substituted with zero, one, or 2fluoro. and, when C_(t) H_(2t) is alkylene, having one to 7 carbonatoms. inclusive, in the chain between --CR_(a) -- and the phenyl ring:R₁ is hydrogen or alkyl of one to 12 carbon atoms, inclusive. cycloalkylof 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms,inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro or alkylof one to 4 carbon atoms, inclusive; R₂ is alkyl of 2 to 10 carbonatoms, inclusive, substituted with zero, one, 2, or 3 fluoro; R₃ ishydrogen or alkyl of one to 4 carbon atoms, inclusive; T is alkyl of oneto 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or OR₁₇,wherein R₁₇ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,and wherein s is zero, one, 2, or 3 with the proviso that not more thantwo T's are other than alkyl.

Each of the phenylene-oxa prostaglandin analogs represented by formulaIV-XI is useful in place of the corresponding known prostaglandins forat least one of their known pharmacological purposes, which includereduction of gastric secretion, inhibition of blood plateletaggregation, increase of nasal patency, and labor inducement at term.

SUMMARY OF THE INVENTION

It is the purpose of this invention to provide intermediates useful inthe preparation of phenyleneoxa prostagladin analogs. It is a furtherpurpose to provide novel processes for preparing these intermediates.

These intermediates include not only those which are useful forpreparing the formula IV-XI analogs as disclosed in the above-identifiedGerman Offenlegungsschrift No. 2,209,990, but also phenylene-oxaprostaglandin analogs represented by the following formulas:

    ______________________________________                                        XV                                                                             ##STR17##                                                                    XVI                                                                            ##STR18##                                                                    XVII                                                                           ##STR19##                                                                    XVIII                                                                          ##STR20##                                                                    ______________________________________                                    

wherein C_(n) H_(2n) represents alkylene of one to 4 carbon atomsinclusive, and wherein R₄ is alkyl of one to 4 carbon atoms, inclusive,substituted with zero, one, 2 or 3 fluoro.

For example, a specific compound illustrating these analog isrepresented by the following formula: ##STR21## The compound of formulaXIX is named3-oxa-5,7-inter-m-phenylene-15(S)-15-methyl-17,18-didehydro-6-nor-PGF.sub.1α,methyl ester.

It is still a further purpose to provide intermediates useful in thepreparation of novel phenylene prostaglandin analogs, including novelprocesses for preparing those intermediates.

As disclosed in a co-filed U.S. Pat. application by Norman A. Nelson,applicant's docket number 2528, those phenylene prostaglandin analogsare represented by the following formulas:

    ______________________________________                                                                    LVIII                                              ##STR22##                                                                                                LIX                                                ##STR23##                                                                                                LX                                                 ##STR24##                                                                                                LXI                                                ##STR25##                                                                    ______________________________________                                    

wherein R₁ and R₃ have the same meaning as for the compounds above.

For convenience these phenylene compounds may be represented by theformulas

    ______________________________________                                                                    LXXII                                              ##STR26##                                                                                                LXXV                                               ##STR27##                                                                    ______________________________________                                    

wherein Q is ##STR28## and R₃ and R₁ are as defined above.

For example, a specific compound illustrating these phenylene analogs isrepresented by the following formula ##STR29## The compound of formulaLXII is named 4,5,6-trinor-3,7-inter-m-phenylene-PGE₁, methyl ester.

Thus, for the phenylene-oxa compounds, there is provided an opticallyactive compound of the formula ##STR30## or a racemic mixture of thatcompound and the enantiomer thereof, wherein C_(p) H_(2p) represents avalence bond or alkylene of one to 4 carbon atoms, inclusive, with oneor 2 carbon atoms in the chain between the phenylene ring and --O--;wherein R₅ and R₆ are alkyl of one to 4 carbon atoms. inclusive, or,when taken together, the group represented by the formula ##STR31##wherein R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ are hydrogen, alkyl of one to 4carbon atoms, inclusive, or phenyl, with the proviso tht not more thanone of the R's is phenyl and the total number of carbon atoms is from 2to 10, inclusive; and x is zero or one; wherein R₁₃ is carboxyacyl ofthe formula ##STR32## wherein R₁₄ is hydrogen, alkyl of one to 19 carbonatoms, inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive, whereinalkyl or aralkyl are substituted with zero to 3 halo atoms; and whereinindicates attachment to the cyclopropane ring in endo or exoconfiguration.

There is further provided an optically active compound of the formula##STR33## or a racemic mixture of that compound and the enantiomerwherein C_(p) H_(2p) is as defined above, indicates attachment to thecyclopropane ring in exo or endo configuration, and R₁₆ is hydrogen or ablocking group, R₁₅, as defined below.

There is further provided an optically active compound of the formula##STR34## or a racemic mixture of that compound and the enantiomerthereof, wherein C_(p) H_(2p) and are as defined above, wherein G is (1)R₂, which represents alkyl of 2 to 10 carbon atoms substituted withzero, one, 2, or 3 fluoro or (2) a monovalent moiety of the formula##STR35## wherein C_(t) H_(2t) represents a valence bond or alkylene ofone to 10 carbon atoms, inclusive, substituted with zero, one, or 2fluoro, said alkylene having one to 7 carbon atoms, inclusive, in thechain between --CR₃ -- and the phenyl ring, wherein T is alkyl of one to4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₁₇,wherein R₁₇ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,and wherein s is zero, one, 2, or 3, with the proviso that not more thantwo T's are other than alkyl; wherein R₁₆ is hydrogen or a blockinggroup, R₁₅ ; and wherein R₃ is hydrogen or alkyl of one to 4 carbonatoms, inclusive.

There is further provided an optically active compound of the formula##STR36## or a racemic mixture of that compound and the enantiomerthereof, wherein C_(p) H_(2p) , R₃, R₁₆, and are as defined above;wherein C_(n) H_(2n) is alkylene of one to 4 carbon atoms, inclusive;and wherein R₄ is alkyl of one to 4 carbon atoms, inclusive, substitutedwith zero, one, 2, or 3 fluoro.

There is further provided an optically active compound of the formula##STR37## or a racemic mixture of that compound and the enantiomerthereof, wherein C_(n) H_(2n), C_(p) H_(2p), and R₄ are as definedabove; wherein Q is ##STR38## wherein R₃ is as defined above; andwherein R₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive,cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbonatoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro oralkyl of one to 4 carbon atoms, inclusive.

There is likewise provided a process for preparing an optically activecompound of the formula ##STR39## or a racemic mixture of that compoundand the enantiomer thereof, wherein C_(p) H_(2p) represents a valencebond or alkylene of one to 4 carbon atoms, inclusive, with one or 2carbon atoms in the chain between the phenylene ring and --O--; whereinR₅ and R₆ are alkyl of one to 4 carbon atoms, inclusive, or, when takentogether ##STR40## wherein R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ are hydrogen,alkyl of one to 4 carbon atoms, inclusive, or phenyl, with the provisothat not more than one of the R's is phenyl and the total number ofcarbon atoms is from 2 to 10, inclusive, and x is zero or one; whereinR₁₃ is carboxyacyl of the formula ##STR41## wherein R₁₄ is hydrogen,alkyl of one to 19 carbon atoms, inclusive, or aralkyl of 7 to 12 carbonatoms, inclusive, wherein alkyl or aralkyl are substituted with zero to3 halo atoms; and wherein indicates attachment to the cyclopropane ringin endo or exo configuration, which comprises reacting an opticallyactive compound of the formula ##STR42## or a racemic mixture of thatcompound and the enantiomer thereof, wherein , R₅ and R₆ are as definedabove, with a compound of the formula ##STR43## wherein C_(p) H_(2p) andR₁₃ are as defined above.

There is further provided a process for preparing an optically activecompound of the formula ##STR44## or a racemic mixture of that compoundand the enantiomer thereof, wherein C_(p) H_(2p) represents a valencebond or alkylene of one to 4 carbon atoms, inclusive, with one or 2carbon atoms in the chain between the phenylene ring and --O--; whereinM is a hydrocarbyl or substituted hydrocarbyl group, being (1) R₂,wherein R₃ is alkyl of 2 to 10 atoms substituted with zero, one, 2, or 3fluoro, (2) a monovalent moiety of the formula ##STR45## wherein C_(t)H_(2t) represents a valence bond or alkylene of one to 10 carbon atoms,inclusive, substituted with zero, one, or 2 fluoro, and, when C_(t)H_(2t) is alkylene, having one to 7 carbon atoms, inclusive, in thechain between --CR₃ -- and the phenyl ring, wherein T is alkyl of one to4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₁₇,wherein R₁₇ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,and wherein s is zero, one, 2, or 3 with the proviso that not more thantwo T's are other than alkyl; or (3) a group represented by the formula##STR46## wherein C_(n) H_(2n) is alkylene of one to 4 carbon atoms,inclusive and R₄ is alkyl of one to 4 carbon atoms, inclusive,substituted with zero, one, 2, or 3 fluoro; and wherein indicatesattachment to the cyclopropane ring in alpha or beta configuration;which comprises treating an optically active compound of the formula##STR47## or a racemic mixture of that compound and the enantiomerthereof wherein R₁₆ is hydrogen or a blocking group R₁₅, and whereinC_(p) H_(2p) and are as defined above, with a Wittig reagent preparedfrom a compound of the formula ##STR48## wherein Hal is chloro, bromo,or iodo, and M and R₃ are as defined above; with the proviso that whenR₁₆ in the product is hydrogen, R₁₅ is replaced with hydrogen.

Likewise, for the phenylene compounds, there is provided an opticallyactive compound of the formula ##STR49## or a racemic mixture of thatcompound and the enantiomer thereof, R₁₉ is hydrogen or alkyl of one to4 carbon atoms inclusive; wherein R₅, R₆, and are as defined above.

There is further provided an optically active compound of the formula##STR50## or a racemic mixture of that compound and the enantiomerthereof, wherein R₁, R₃, and are as defined above, and wherein R₁₆ ishydrogen or a blocking group R₁₅ as defined herein.

There is further provided a process for preparing an optically activecompound of the formula ##STR51## or a racemic mixture of that compoundand the enantiomer thereof, wherein R₅, R₆, R₁₉, and are as definedabove, by reacting an optically active compound of the formula ##STR52##or a racemic mixture of that compound and the enantiomer thereof,wherein R₅, R₆, and are as defined above, with a compound of the formula##STR53## wherein R₁₉ is as defined above.

There is further provided a process for preparing an optically activecompound of the formula ##STR54## or a racemic mixture of that compoundand the enantiomer thereof, wherein R₅, R₆, R₁₉, and are as definedabove and wherein R₁₈ represents hydrogen, carboxyacyl R₁₃ as definedabove; benzoyl and substituted benzoyl as represented by wherein T isalkyl of one to 4 carbon atoms, inclusive, phenylalkyl of 7 to 10 carbonatoms, inclusive, or nitro, and s is zero to 5, inclusive, provided thatnot more than two T's are other than alkyl, and that the total number ofcarbon atoms, in the T's does not exceed 10 carbon atoms;mono-esterified phthaloyl as represented by ##STR55## wherein R₃ isalkyl of one to 4 carbon atoms, inclusive; or naphthoyl and substitutednaphthoyl as represented by ##STR56## wherein T and s are as definedabove; by (1) hydrogenating an optically active compound of the formula##STR57## or a racemic mixture of that compound and the enantiomerthereof, wherein R₅, R₆, R₁₉, and are as defined above. in the presenceof a noble metal catalyst so as to obtain a compound of the formula##STR58## or a racemic mixture of that compound and the enantiomerthereof, wherein R₅, R₆, R₁₉, and are as defined above, and (2) reactingthe product of step (1) with an acylating agent.

The above novel intermediates of formulas XX-XXV and LXIII-LXVI aretransformed into the products of formulas IV-XVIII and LVIII-LXI byprocesses described below.

With regard to formulas IV to XVIII andd XX to XXV, examples of alkyl ofone to 4 carbon atoms, inclusive are methyl, ethyl, propyl, butyl, andisomeric forms thereof. Examples of alkyl of one to 12 carbon atoms,inclusive, are those given above, and pentyl, hexyl, heptyl, octyl,nonyl, decyl, undecyl, dodecyl, and isomeric forms thereof. Examples ofalkyl of one to 19 carbon atoms, inclusive, are those given above, andtridecyl, tetradecyl, pentadecyl, hexadecyl, octadecyl, nonadecyl, andisomeric forms thereof. Examples of cycloalkyl of 3 to 10 carbon atoms,inclusive, which includes alkyl-substituted cycloalkyl, are cyclopropyl,2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl,2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butyl-cyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkylof 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl,1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl,2-(1-naphthylethyl), and 1-(2-napthylmethyl). Examples of phenylsubstituted by one to 3 chloro or alkyl of one to 4 carbon atoms,inclusive, are p-chlorophenyl, m-chlorophenyl, o-chlorophenyl,2,4-dichlorophenyl, 2,4,6-trichlorophenyl, β-tolyl, m-tolyl, o-tolyl,p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl,4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

Examples of alkyl of one to 10 carbon atoms, inclusive, substituted withone to 3 fluoro, are trifluoromethyl, 2-fluoroethyl, 2-fluorobutyl,3-fluorobutyl, 4-fluorobutyl, 5-fluoropentyl, 4-fluoro-4-methylpentyl,3-fluoroisoheptyl, 8-fluorooctyl, 3,4-difluorobutyl, 4,4-difluoropentyl,5,5-difluoropentyl, 5,5,5-trifluoropentyl, and 10,10,10-trifluorodecyl.

Examples of alkylene within the various scopes of C_(p) H_(2p), C_(n)H_(2n), and C_(t) H_(2t), as those are defined above, are methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,and heptamethylene, and those alkylene with one or more alkylsubstituents on one or more carbon atoms thereof, e.g., --CH(CH₃)--,--C(CH₃)₂ --.

Examples of alkylene of one to 4 carbon atoms, inclusive, with one or 2carbon atoms in the chain are methylene, ethylene, --CH(CH₃)--,--C(CH₃)₂ --, --CH(CH₂ CH₃)--, --CH₂ --CH(CH₃)--, --CH(CH₃ --CH(CH₃)--,and --CH₂ --C(CH₃)₂ --. Examples of alkylene of one to 4 carbon atoms,inclusive, include those given above, and trimethylene andtetramethylene. Examples of alkylene of one to 9 carbon atoms,inclusive, with one to 5 carbon atoms inclusive, in the chain includethose given above, pentamethylene, and --CH(CH₃)--CH₂ --; --C(CH₃)₂--CH₂ --, --CH₂ --CH(CH₃ --CH₂ --, --CH₂ --CH₂ --CH(CH₂ CH₃)--, --CH₂--CH₂ --CH(CH₂ CH₂ CH₃)--, --CH(CH₃)--CH(CH₃)--CH₂ --CH₂₋₋, --CH₂ --CH₂--CH₂ --C(CH₃)₂ --CH₂ --, --(CH₂)₄ --CH(CH.sub. 3)--, and --C(CH₃)₂--CH₂ --CH₂ --CH₂ --CH₂ --C(CH₃)₂ --. Examples of alkylene of one to 10carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, andhaving one to 7 carbon atoms, inclusive, in the chain, include thosegiven above, hexamethylene, heptamethylene, and --C(CH₃)₂ --(CH₂)₃ --,--C(CH₃)₂ --(CH₂)₄ --, --C(CH₃)₂ --(CH₂)₅ --, --C(CH₃)₂ --(CH₂)₆ --,--CHF--CH₂ --, --CHF--CHF--, --CF₂ --CH₂ --, --CF₂ --CH₂ --CH₂ --, -CH₂-CH₂ --CF₂ --, --CH₂ --CHF--CH₂ --, --CH₂ --CH₂ --CF(CH₃)--, --(CH₂)₃--CF₂ --, --CF₂ --(CH₂)₃ --, --CF₂ --(CH₂)₆ --and --CHF--(CH₂)₆ --.

Examples of ##STR59## as defined above are phenyl, p-tolyl, m-tolyl,o-tolyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-chlorophenyl,m-chlorophenyl, o-chlorophenyl, p-trifluoromethylphenyl,m-trifluoromethylphenyl, o-trifluoromethylphenyl, p-hydroxyphenyl,o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-ethoxyphenyl,m-isopropoxyphenyl, o-ethylphenyl, m-isopropylphenyl,p-tert-butylphenyl, p-butoxyphenyl, 3,4-dimethylphenyl,2,4-diethylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethylphenyl,2,4-dichlorophenyl, 3,4-difluorophenyl, 2-chloro-4-methylphenyl,2-fluoro-4-methoxyphenyl, 3,5-dimethyl-4-fluorophenyl,2,6-dimethyl-4-hydroxyphenyl, and 2,4-di(trifluoromethyl)phenyl.

The novel intermediates of this invention, including the formulaXX-XXVIII compounds above, are useful for preparing the analogs offormula IV--XI above. The pharmacological utility of the end-products isdisclosed in the above-identified German Offenlegungsschrift No.2,209,990. Certain ones of these intermediates are also useful inpreparing the analogs of formula XV-XVIII. Those analogs are not thesubject of this invention, but each of them is useful in place of thecorresponding known prostaglandins for at least one of their knownpharmacological purposes.

In accordance with the preferences disclosed in the above-identifiedGerman Offenlegunsschrift for certain compounds within the scope offormulas IV--XI, certain of the novel intermediates of this inventionare preferred. For example, in the compounds of formulas XX, XXI, andXXII, C_(p) H_(2p) is preferably a valence bond or methylene; likewise,is preferably endo. In the compounds of formulas XXII wherein G is R₂,it is preferred that R₂ be ##STR60## wherein C_(g) H_(2g) is alkylene ofone to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive,in the chain between --CR₂₁ R₂₂ -- and terminal methyl, wherein R₂₁ andR₂₂ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro,being the same or different with the proviso that R₂₂ is fluoro onlywhen R₂₁ is hydrogen or fluoro. Especially preferred are thoseformula-XXII compounds wherein R₂ is --CHF--(CH₂)₃ --CH₃, --CF₂ --(CH₂)₃--CH₃, --CH(CH₃)--(CH₂)₃ --CH₃, --C(CH₃)₂ --(CH₂)₃ --CH₃, or --C(C₂ H₅)₂--(CH₂)₃ --CH₃. In the compounds of formula XXII wherein G is ##STR61##it is preferred that C_(t) H_(2t) be a valence bond or alkylene or oneto 4 carbon atoms, inclusive, i.e. --(CH₂)_(d) --wherein d is one, 2, 3,or 4, with or without fluoro or alkyl substituted carbon (C-15), e.g.--CHF--(CH₂)_(e) --, --CF₂ --(CH₂)_(e) --, --CH(CH₃)-(CH₂)_(e) --, or--C(CH₃)₂ --(CH₂)_(e) --, wherein e is zero, one, 2, or 3. In thecompounds of formula XXII, R₃ is preferably hydrogen or methyl.

In compounds of formulas XXIII and XXIV it is preferred that C_(p)H_(2p) be a valence bond or methylene, that C_(n) H_(2n) be methyleneand that R₄ be ethyl to yield preferred compounds of formulas XV-XVIII.

Reference to Chart A will make clear the steps by which startingmaterial XXX is transformed to product XXXVI. The formula-XXX compoundwherein R₅ and R₆ together are --CH₂ --C(CH₃)₂ --CH₂ -- and is endo,i.e. bicyclo [3.1.0]hex-2-ene-6-endo-carboxaldehyde neopentyl glycolacetal, is available either in racemic or optically active form. SeeU.S. Pat. No. 3,711,515 for both the endo and exo forms.

In Chart A the symbols used therein have the same meanings as definedabove, as to C_(p) H_(2p), G, ₁, R₁, R₃, R₅, R₆, R₁₃, R₁₆, R₁₈, and .

    ______________________________________                                        CHART A                                                                       ______________________________________                                                                     XXX                                               ##STR62##                                                                                                 XX                                                ##STR63##                                                                                                 XXXI                                              ##STR64##                                                                                                 XXXII                                             ##STR65##                                                                                                 XXI                                               ##STR66##                                                                                                 XXII                                              ##STR67##                                                                                                 XXXIII                                            ##STR68##                                                                    XXXIV                                                                          ##STR69##                                                                    XXXV                                                                           ##STR70##                                                                    XXXVI                                                                          ##STR71##                                                                    ______________________________________                                    

furthermore, in Chart A and likewise in the other charts of thisspecification, the formulas as drawn represent specific optical isomersfollowing the conventions applied herein to the end products. However,for purposes of convenience and brevity it is intended that suchrepresentations of the process steps for the optically activeintermediates are applicable to those same process steps as used for thecorresponding racemic intermediates.

Both the endo and exo forms of bicyclo hexene XXX are available or aremade by methods known in the art, in either their racemic or opticallyactive forms. See U.S. Pat. No. 3,711,515. Either the endo or exostarting material will yield the ultimate analogs of formula XXXVI bythe processes of Chart A.

In step (a) oxetane XX is obtained by reaction of the formula-XXXbicyclo hexene with an aldehyde of the formula ##STR72## wherein C_(p)H_(2p) represents a valence bond or alkylene of one to 4 carbon atoms,inclusive, with one or 2 carbon atoms in the chain between the phenylring and --O--, and wherein R₁₃ is carboxyacyl of the formula ##STR73##wherein R₁₄ is hydrogen, alkyl of one to 19 carbon atoms, inclusive, oraralyky of 7 to 12 carbon atoms, inclusive, wherein alkyl or aralkyl aresubstituted with zero to 3 halo atoms.

The formula-XXVI aldehydes are available or readily prepared by methodsknown in the art. Examples of such compounds within the scope of formulaXXVI are: ##STR74##

The formation of oxetane XX is accomplished by photolysis of a mixtureof the bicyclo hexene and the aldehyde in a solvent. The bicyclo hexeneis preferably used in excess over the molar equivalent, for example 2 to4 times the theoretical equivalent amount. The solvent is aphotochemically inert organic liquid, for example liquid hydrocarbons,including benzene or hexane, 1,4-dioxane, and diethyl ether. Thereaction is conveniently done at ambient conditions, for example 25° C.,but may be done over a wide range of temperature, from about -78° C. tothe boiling point of the solvent. The irradiation is done with mercuryvapor lamps of the low or medium pressure type, for example thosepeaking at 3500 A. Such sources are available from The Southern NewEngland Ultraviolet Co., Middletown, Conn. Alternatively, those lampswhich emit a broad spectrum of wavelengths and which may be filtered totransmit only light of λ 3000-3700 A may also be used. For a review ofphotolysis see D. R. Arnold in "Advances in Photochemistry", Vol. 6, W.A. Noyes et al., Wiley-Interscience, New York, 1968, pp. 301-423.

In step (b) the cleavage of the oxetane ring to yield the formula-XXXIcompounds is accomplished with an alkali metal in the presence of aprimary amine or alcohol. Preferred is lithium in ethylamine, or sodiumin ethyl alcohol. See L. J. Altman et al., Synthesis 129 (1974). Thecleavage transformation may also be accomplished by catalytichydrogenation over an inert metal catalyst, e.g. Pd on carbon, in ethylacetate or ethanol.

In step (c) the formula XXXI diol is prepared for step (d) by preferablyblocking the two hydroxyl groups with carboxyacyl groups within thescope of R₁₃ as defined above, i.e. R₁₄ C(O)-- wherein R₁₄ is hydrogen,alkyl of one to 19 carbon atoms, inclusive, or aralkyl of 7 to 12 carbonatoms, inclusive, wherein alkyl or aralkyl are substituted with zero to3 halo atoms. For example, the diol is treated with an acid anhydridesuch as acetic anhydride, or with an acyl halide in a tertiary amine.Especially preferred is pivaloyl chloride in pyridine.

Other carboxyacylating agents useful for this transformation are knownin the art or readily obtainable by methods known in the art, andinclude carboxyacyl halides, preferably chlorides, bromides, orfluorides, i.e. R₁₄ C(O)Cl, R₁₄ C(O)Br, or R₁₄ C(O)F, and carboxyacidanhydrides, ##STR75## wherein R₁₄ is as defined above. The preferredreagent is an acid anhydride. Examples of acid anhydrides useful forthis purpose are acetic anhydride, propionic anhydride, butyricanhydride, pentanoic anhydride, nonanoic anhydride, tridecanoicanhydride, stearic anhydride, (mono, di, or tri) chloroacetic anhydride,3-chlorovaleric anhydride, 3-(2-bromoethyl)-4,8-dimethylnonanoicanhydride, cyclopropaneacetic anhydride, 3-cycloheptanepropionicanhydride, 13-cyclopentanetridecanoic anhydride, phenylacetic anhydride,(2 or 3)-phenylpropionic anhydride, 13-phenyltridecanoic anhydride, andphenoxyacetic anhydride. The choice of anhydride depends upon theidentity of R₁₄ in the final acylated product, for example when R₁₄ isto be methyl, acetic anhydride is used; when R₁₄ is to be 2-chlorobutyl,3-chlorovaleric anhydride is used.

When R₁₄ is hydrogen, ##STR76## is formyl. Formylation is carried out byprocedures known in the art, for example, by reaction of the hydroxycompound with the mixed anhydride of acetic and formic acids or withformylimidazole. See, for example, Fieser et al., Reagents for OrganicSynthesis, John Wiley and Sons, Inc., pp. 4 and 407 (1967) andreferences cited therein. Alternatively, the formula XXXI diol isreacted with two equivalents of sodium hydride and then with excessethyl formate.

In formula XXXII, R₁₈ may also represent a blocking group such asbenzoyl, substituted benzoyl, mono-esterified phthaloyl, naphthoyl andsubstituted naphthoyl. For introducing those blocking groups, methodsknown in the art are used. Thus, an aromatic acid of the formula R₁₈ OH,wherein R₁₈ is as defined above, for example benzoic acid, is reactedwith the formula-XXXI compound in the presence of a dehydrating agent,e.g. sulfuric acid, zinc chloride, or phosphoryl chloride; or ananhydride of the aromatic acid of the formula (R₁₈)₂ O, for examplebenzoic anhydride, is used.

As examples of reagents providing R₁₈ for the purposes of thisinvention, the following are available as acids (R₁₈ OH), anhydrides((R₁₈)₂ O), or acyl chlorides (R₁₈ Cl): benzoyl; substituted benzoyl,e.g. (2-, 3-, or 4-)methylbenzoyl, (2-, 3-, or 4-)ethylbenzoyl, (2-, 3-,or 4-)isopropylbenzoyl, (2-, 3-, or 4-)tert-butylbenzoyl,2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl,2,4,6-trimethylbenzoyl, pentamethylbenzoyl, α-phenyl-(2-, 3-, or4-(toluyl, 2-, 3-, or 4-) 4-phenethylbenzoyl, 2-, 3-, or 4-nitrobenzoyl,(2,4-, 2,5-, or 3,5-)dinitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl,2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl; mono-esterifiedphthaloyl, e.g. ##STR77## (1- or 2-)naphthoyl; and substitutednaphthoyl, e.g. (2-, 3-, 4-, 5-, 6-, or 7-)-methyl-1-naphthoyl, (2-or4-)ethyl-1-naphthoyl, 2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl,6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl,8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 8-)-nitro-1-naphthoyl,4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7- or 8-)-methyl-1-naphthoyl,4-ethyl-2-naphthoyl, and (5- or 8-)-nitro-2-naphthoyl.

Examples of aromatic acid anhydrides useful for this purpose are benzoicanhydride, (o, m, or p)-bromobenzoic anhydride, 2,4 (or3,4)-dichlorobenzoic anhydride, p-trifluoromethylbenzoic anhydride,2-chloro-3-nitrobenzoic anhydride, (o, m, or p)-nitrobenzoic anhydride,(o, m, or p)-toluic anhydride, 4-methyl-3-nitrobenzoic anhydride,4-octylbenzoic anhydride, (2,3, or 4)-biphenylcarboxylic anhydride,3-chloro-4-biphenylcarboxylic anhydride,5-isopropyl-6-nitro-3-biphenylcarboxylic anhydride, and (1 or2)-naphthoic anhydride.

Preferably, however, an acyl halide, e.g. R₁₈ Cl, for example benzoylchloride, is reacted with the formula-XXXI compound in the presence of atertiary amine such as pyridine, triethylamine, and the like. Thereaction is carried out under a variety of conditions using proceduresgenerally known in the art. Generally, mild conditions are employed,e.g. 20°-60° C., contacting the reactants in a liquid medium, e.g.excess pyridine or an inert solvent such as benzene, toluene orchloroform. The acylating agent is used either in stoichiometric amountor in excess.

There may be employed, therefore, benzoyl chloride, 4-nitrobenzoylchloride, 3,5-dinitrobenzoyl chloride, and the like, i.e. R₁₈ Clcompounds corresponding to the above R₁₈ groups. If the acyl chloride isnot available, it is made from the corresponding acid and phosphoruspentachloride as is known in the art.

In step (d), the formula-XXXII acetal is converted to aldehyde XXI byacid hydrolysis, known in the art, using dilute mineral acids, acetic orformic acids, and the like. Solvents such as acetone, dioxane, andtetrahydrofuran are used.

For steps (e) through (h) it is optional whether R₁₆ be hydrogen or a"blocking group" as defined below. For efficient utilization of theWittig reagent it is preferred that R₁₆ be a blocking group. If theformula-XXXII compound is used wherein R₁₈ is hydrogen, the formula-XXIintermediate will have hydrogen at R₁₆. If R₁₆ is to be a blockinggroup, that may be readily provided prior to step (e) by reaction withsuitable reagents as discussed below.

The blocking group, R₁₅, is any group which replaces hydrogen of thehydroxyl groups, which is not attacked by nor is reactive to thereagents used in the respective transformations to the extent that thehydroxyl group is, and which is subsequently replaceable by hydrogen ata later stage in the preparation of the prostaglandin-like products.

Several blocking groups are known in the art, e.g. tetrahydropyranyl,acetyl, and p-phenylbenzoyl (see Corey et al., J. Am. Chem. Soc. 93,1491 (1971)).

Those which have been found useful include (a) carboxyacyl within thescope of R₁₃ above, i.e. acetyl, and also benzoyl, naphthoyl, and thelike; (b) tetrahydropyranyl; (c) tetrahydrofuranyl; (d) a group of theformula ##STR78## wherein R₂₆ is alkyl of one to 18 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one,2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₂₇ and R₂₈are the same or different, being hydrogen, alkyl of one to 4 carbonatoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkylof one to 4 carbon atoms, inclusive, or, when R₂₇ and R₂₈ are takentogether, --(CH₂)_(a) -- or --(CH₂)_(b) -O-(CH₂)_(c) -- wherein a is 3,4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso thatb plus c is 2, 3, or 4, and wherein R₂₉ is hydrogen or phenyl; or (e)-Si(A)₃ wherein A is alkyl of one to 4 carbon atoms, inclusive, phenyl,phenyl substituted with one or 2 fluoro, chloro, or alkyl of one to 4carbon atoms, inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive.

In replacing the hydrogen atoms of the hydroxyl groups with carboxyacyl,benzoyl, naphthoyl, etc. blocking groups, methods known in the art areused. The reagents and conditions are discussed above for R₁₈ oncompound XXXII.

When the blocking group is tetrahydropyranyl or tetrahydrofuranyl, theappropriate reagent, e.g. 2,3-dihydropyran or 2,3-dihydrofuran, is usedin an inert solvent such as dichloromethane, in the presence of an acidcondensing agent such as p-toluenesulfonic acid or pyridinehydrochloride. The reagent is used in slight excess, preferably 1.0 to1.2 times theory. The reaction is carried out at about 20°-50° C.

When the blocking group is of the formula ##STR79## as defined above,the appropriate reagent is a vinyl ether, e.g. isobutyl vinyl ether orany vinyl ether of the formula R₂₆ -O-C(R₂₇)=CR₂₈ R₂₉ wherein R₂₆, R₂₇,R₂₈, and R₂₉ are as defined above; or an unsaturated cyclic orheterocyclic compound, e.g. 1-cyclohex-1-yl methyl ether ##STR80## or5,6-dihydro-4-methoxy-2H-pyran ##STR81## See C. B. Reese et al., J. Am.Chem. Soc. 89, 3366 (1967). The reaction conditions for such vinylesters and unsaturates are similar to those for dihydropyran above.

When the blocking group is silyl of the formula --Si(A)₃, theformula-XXI compound is transformed to a silyl derivative of formula XXIby procedures known in the art. See, for example, Pierce, "Silylation ofOrganic Compounds," Pierce Chemical Co., Rockford, Ill. (1968). Thenecessary silylating agents for these transformations are known in theart or are prepared by methods known in the art. See, for example, Post"Silicones and Other Organic Silicon Compounds," Reinhold PublishingCorp., New York, N.Y. (1949). These reagents are used in the presence ofa tertiary base such as pyridine at temperatures in the range of about0° to +50° C. examples of trisubstituted mono-chlorosilanes suitable forthis purpose include chlorotrimethylsilane, chlorotriisobutylsilane,chlorotriphenylsilane, chlorotris(p-chlorophenyl)silane,chlorotri-m-tolylsilane, and tribenzylchlorosilane. Alternately, achlorosilane is used with a corresponding disilazane. Examples of othersilylating agents suitable for forming the formula-XXI intermediatesinclude pentamethylsilylamine, pentaethylsilylamine,N-trimethylsilydiethylamine, 1,1,1-triethyl-N,N-dimethylsilylamine,N,N-diisopropyl-1,1,1,-trimethylsilylamine,1,1,1-tributyl-N,N-dimethylsilylamine,N,N-dibutyl-1,1,1-trimethylsilylamine,1-isobutyl-N,N,1,1-tetramethylsilylamine,N-benzyl-N-ethyl-1,1,1-trimethylsilylamine,N,N,1,1-tetramethyl-1-phenylsilylamine,N,N-diethyl-1,1-dimethyl-1-phenylsilylamine,N,N-diethyl-1-methyl-1,1-diphenylsilylamine,N,N-dibutyl-1,1,1-triphenylsilylamine, and1-methyl-N,N,1,1-tetraphenylsilylamine.

In step (e) the aldehyde group is transformed by the Wittig reaction toa moiety of the formula -CH=CR₃ G. For this purpose a phosphonium saltprepared from an organic chloride or bromide of the formula ##STR82## isemployed, wherein G and R₃ are as defined above. These organic chloridesor bromides are known in the art or are readily prepared by methodsknown in the art. See for example the above-identified GermanOffenlegungsschrift No. 2,209,990. As to the Wittig reaction, see, forexample. U.S. Pat. No. 3,776,941 and references cited therein.

In step (f) compound XXXIII is obtained by deblocking if necessary. WhenC_(p) H_(2p) is a valence bond, and R₁₆ is a hindered carboxyacyl, e.g.##STR83## R₁₅ on the phenolic hydroxy is selectively replaced withhydrogen by hydrolysis with sodium or potassium hydroxide inethanol-water. Instead of ethanol, other water-miscible solvents may besubstituted, for example 1,4-dioxane, tetrahydrofuran, or1,2-dimethoxyethane. The selective hydrolysis is preferably carried outat -15° to 25° C. Higher temperatures may be used but with some decreasein selectivity.

Total hydrolysis of R₁₆ blocking groups on compound XXII isaccomplished, when R₁₆ is carboxyacyl, with an alkali alkoxide in analcoholic solvent, preferably sodium methoxide in methanol at atemperature from 25° C. to reflux. When R₁₆ is tetrahydropyranyl,aqueous acid, e.g. dilute acetic acid, is used at 25° to 50° C. When R₁₆is trialkylsilyl, either aqueous acid or base are used at 25° to 50° C.

Continuing with Chart A, in step (g) a Williamson synthesis is employedto obtain compound XXXIV. The formula-XXXIII alcohol or phenol iscondensed with a haloacetate within the scope of Hal-CH₂ -COOR₁ whereinHal is chloro, bromo, or iodo and R₁ is as defined above. Normally thereaction is done in the presence of a base such as n-butyllithium,phenyllithium, triphenylmethyllithium, sodium hydride, potassiumt-butoxide, sodium hydroxide, or potassium hydroxide.

The transformation from compound XXXIV to product XXXVI may beaccomplished by any of several routes known in the art. See U.S. Pat.No. 3,711,515. Thus, by step (h), the alkene XXXIV is hydroxylated toglycol XXXV. For this purpose osmium tetroxide is a suitable reagent,for example in conjunction with N-methylmorpholine oxide-hydrogenperoxide complex (see Fieser et al., "Reagents for Organic Synthesis",p. 690, John Wiley and Sons, Inc., New York (1967)). Thereafter, severalmethods are available for obtaining the formula-XXXVI product. In onemethod the glycol is converted to a bis(alkanesulfonic acid) ester andsubsequently hydrolyzed to XXXVI by methods known in the art (see, forexample German Offenlegungsschrift No. 1,937,676, Derwent Farmdoc6862R); see also U.S. Pat. 3,843,712. Another method is by way of adiformate by formolysis of the glycol (see U.S. Pat. No. 3,711,515).

Still another method is by way of a cyclic ortho ester. For thispurpose, glycol XXXV is reacted with an ortho ester of the formula##STR84## wherein R₂₄ is hydrogen, alkyl of one to 19 carbon atoms,inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive, substitutedwith zero to 3 halo atoms; and R₂₅ is methyl or ethyl. There is thenformed a cyclic ortho ester of the formula ##STR85## wherein C_(p)H_(2p) G, R₁, R₃, R₁₆, R₂₄, R₂₅, and are as defined above. The reactiongoes smoothly in a temperature range of -50° C. to -100° C., althoughfor convenience 0° C. to +50° C. is generally preferred. From 1.5 to 10molar equivalents of the ortho ester are employed, together with an acidcatalyst. The amount of the catalyst is usually a small fraction of theweight of the glycol, say 1% and typical catalysts include pyridinehydrochloride, formic acid, hydrogen chloride, p-toluenesulfonic acid,trichloroacetic acid, or trifluoroacetic acid. The reaction ispreferably run in a solvent, for example benzene, dichloromethane, ethylacetate, or diethyl ether. It is generally completed within a fewminutes and is conveniently followed by TLC (thin layer chromatographyon basic silica gel plates).

The ortho ester reagents are known in the art or readily available bymethods known in the art. See for example S. M. McElvain et al., J. Am.Chem. Soc. 64, 1925 (1942), starting with an appropriate nitrile.Examples of useful ortho esters include:

trimethyl orthoformate,

triethyl orthoacetate,

triethyl orthopropionate,

trimethyl orthobutyrate,

triethyl orthovalerate,

trimethyl orthooctanoate,

trimethyl orthophenylacetate, and

trimethyl ortho (2,4-dichlorophenyl)acetate.

Preferred are those ortho esters wherein R₂₄ is alkyl of one to 7 carbonatoms; especially preferred are those wherein R₂₄ is alkyl of one to 4.

Next, the cyclic orthoester LI is reacted with anhydrous formic acid toyield a diol diester of the formula ##STR86## wherein C_(p) H_(2p), G,R₁, R₃, R₁₆, R₂₄, and are as defined above.

By "anhydrous formic acid" is meant that it contains not more than 0.5%water. The reaction is run with an excess of formic acid, which mayitself serve as the solvent for the reaction. Solvents may be present,for example dichloromethane, benzene, or diethyl ether, usually not over20% by volume of the formic acid. There may also be present organic acidanhydrides, for example acetic anhydride, or alkyl orthoesters, forexample trimethyl orthoformate, which are useful as drying agents forthe formic acid. Although the reaction proceeds over a wide-range oftemperatures, it is conveniently run at about 20-30° C. and is usuallycompleted within about 10 minutes.

Finally, the diol diester LII is converted to product XXXVI by methodsknown in the art, for example by hydrolysis in the presence of a base inan alcoholic medium. Examples of the base are sodium or potassiumcarbonate or sodium or potassium alkoxides including methoxides orethoxides. The reaction is conveniently run in an excess of thesolvolysis reagent, for example methanol or ethanol. The temperaturerange is from -50° C. to 100° C. The time for completion of the reactionvaries with the nature of R₂₄ and the base, proceeding in the case ofalkali carbonates in a few minutes when R₂₄ is hydrogen but taking up toseveral hours when R₂₄ is ethyl, for example.

When the solvolysis proceeds too long or when conditions are too severe,ester groups at R₁ may be removed. They are, however, readily replacedby methods known in the art. For example, the alkyl, cycloalkyl, andaralkyl esters are prepared by interaction of the formula-XXXVI acidswith the appropriate diazohydrocarbon. For example, when diazomethane isused, the methyl esters are produced. Similar use of diazoethane,diazobutane, 1-diazo-2-ethylhexane, diazocyclohexane, andphenyldiazomethane, for example, gives the ethyl, butyl, 2-ethylhexyl,cyclohexyl, and benzyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing asolution of a diazohydrocarbon in a suitable inert solvent, preferablydiethyl ether, with the acid reactant, advantageously in the same or adifferent inert diluent. After the esterification reaction is complete,the solvent is removed by evaporation, and the ester purified if desiredby conventional methods, preferably by chromatography. It is preferredthat contact of the acid reactants with the diazohydrocarbon be nolonger than necessary to effect the desired esterification, preferablyabout one to about ten minutes, to avoid undesired molecular changes.Diazohydrocarbons are known in the art or can be prepared by methodsknown in the art. See, for example Organic Reactions, John Wiley & Sons,Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).

An alternative method for esterification of the carboxyl moietycomprises transformation of the free acid to the corresponding silversalt, followed by interaction of that salt with an alkyl iodide.Examples of suitable iodides are methyl iodide, ethyl iodide, butyliodide, isobutyl iodide, tert-butyl iodide, cyclopropyl iodide,cyclopentyl iodide, benzyl iodide, phenethyl iodide, and the like. Thesilver salts are prepared by conventional methods, for example, bydissolving the acid in cold dilute aqueous ammonia, evaporating theexcess ammonia at reduced pressure, and then adding the stoichiometricamount of silver nitrate.

The phenyl and substituted phenyl esters are prepared by silylating theacid to protect the hydroxy groups, for example, replacing each --OHwith --O-Si-(CH₃)₃. Doing that may also change --COOH to --COO-Si(CH₃)₃.A brief treatment of the silylated compound with water will change--COO-Si-(CH₃)₃ back to --COOH. Procedures for this silylation are knownin the art. Then, treatment of the silylated compound with oxalylchloride gives the acid chloride which is reacted with phenol or theappropriate substituted phenol to give a silylated phenyl or substitutedphenyl ester. Then the silyl groups, e.g., --O--Si--(CH₃)₃ are changedback to --OH by treatment with dilute acetic acid. Procedures for thesetransformations are known in the art.

Referring to Chart B, there are shown process steps by which theformula-XXX bicyclo hexene is transformed first to an oxetane XXXVIIwith a fully developed side chain

    ______________________________________                                        CHART B                                                                       XXX                                                                            ##STR87##                                                                     ##STR88##                                                                    XXXVII                                                                         ##STR89##                                                                     ##STR90##                                                                    XXXVIII                                                                        ##STR91##                                                                     ##STR92##                                                                    XXXIX                                                                          ##STR93##                                                                     ##STR94##                                                                    XL                                                                             ##STR95##                                                                     ##STR96##                                                                    XLI                                                                            ##STR97##                                                                     ##STR98##                                                                    XLII                                                                           ##STR99##                                                                    XLIII                                                                          ##STR100##                                                                    ##STR101##                                                                    ##STR102##                                                                   XLIV                                                                           ##STR103##                                                                    ##STR104##                                                                   XLV                                                                            ##STR105##                                                                   ______________________________________                                    

and ultimately to a PGE analog. In Chart B, R₁₉ is hydrogen or alkyl ofone to 4 carbon atoms, inclusive, and R₂₀ is hydrogen, alkyl of one to 4carbon atoms, inclusive, or silyl of the formula (A)₃ Si--wherein A isas defined herein above.

In step (a) of Chart B, there is employed an aldehyde of the formula##STR106## wherein C_(p) H_(2p) and R₁₃ are as defined above. Suchaldehydes are available or readily prepared by methods known in the art.Examples of such compounds include: ##STR107##

The conditions for step (a) of Chart B are essentially the same as forstep (a) of Chart A. Thereafter, step (b) for cleavage of the oxetanering, steps (c) and (d) leading to the formula-XL aldehyde, and theWittig reaction of step (e) are similar to and employ the sameconditions as the corresponding steps of Chart A discussed above.

Referring to step (g) of Chart B, the hydroxyl on the cyclopentane ringat the C-9 position is oxidized to an oxo group.

Oxidation reagents useful for this transformation are known in the art.A useful reagent for this purpose is the Jones reagent, i.e., acidifiedchromic acid. See J. Chem. Soc. 30 (1946). A slight excess beyond theamount necessary to oxidize the C-9 secondary hydroxy groups of theformula-XLII reactant is used. Acetone is a suitable diluent for thispurpose. Reaction temperatures at least as low as about 0° C. should beused. Preferred reaction temperatures are in the range 0° to -50° C.Another useful reagent for this purpose is the Collins reagent, i.e.chromium trioxide in pyridine. See J. C. Collins et al., TetrahedronLett., 3363 (1968). Dichloromethane is a suitable diluent for thispurpose. Reaction temperatures of below 30° C. should be used. Preferredreaction temperatures are in the range 0° to +30° C. The oxidationproceeds rapidly and is usually complete in about 5 to 20 minutes.

Examples of other oxidation reagents useful for this transformation aresilver carbonate on Celite (Chem. Commun. 1102 )1969)), mixtures ofchromium or trioxide and pyridine J. Am. Chem. Soc. 75, 422 (1953), andTetrahedron, 18, 1351 (1962)), t-butychromate in pyridine (Biochem. J.84, 195 (1962)), mixtures of sulfur trioxide in pyridine anddimethylsulfoxide (J. Am. Chem. Soc. 89, 5505 (1967)), and mixtures ofdicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87,5661 (1965)).

Step (h) of Chart B and subsequent steps by which the product XLV isobtained are similar to and employ the same conditions at thecorresponding steps of Chart A discussed above.

Referring next to Chart C the process steps are shown whereby aldehydeXXI of Chart A is transformed to a 17,18-tetradehydro-PG analog XXIV anda 17,18-didehydro-PG analog L.

In step (a) of Chart C, a Wittig reagent is employed which is preparedfrom a phosphonium salt of a haloalkyne of the formula

Cl--CHR₃ --C_(n) H_(2n) --C.tbd.C--R₄ or

Br--CHR₃ --C_(n) H_(2n) --C.tbd.C--R₄

wherein C_(n) H_(2n), R₃, and R₄ are as defined above. See, for example,U. Axen et al., Chem. Comm. 1969, 303, and ibid. 1970, 602.

Thereafter, in steps (b) to (d) and subsequent steps yielding the17,18-tetradehydro compound XXIV, the reagents ##STR108## and conditionsare similar to those employed for the corresponding reactions shown inChart A.

Transformation of XXIV to the formula-L compounds is accomplished byhydrogenation of XXIV using a catalyst which catalyzes hydrogenation of--C.tbd.C--only to cis--CH=CH--, as known in the art. See, for example,Fieser et al., "Reagents for Organic Syntheses," pp. 566-567, John Wileyand Sons, Inc., New York (1967). Preferred is Lindlar catalyst in thepresence of quinoline, see Axen, references cited.

Referring next to Chart D there are shown process steps leading tointermediate LVII: ##STR109## wherein C_(p) H_(2p), R₁, R₅, R₆, R₁₈, andare as defined above for Chart A. Furthermore, in Chart D, G has thesame definition as for Charts A, B, and C above.

In step (a) of Chart D, the oxetane ring of compound XX is cleaved bycatalytic hydrogenation, for example in the presence of a noble metalcatalyst such as palladium on carbon. Useful solvents for such areaction include lower alkyl alcohols, e.g. methanol, ethanol,isopropanol, and butanol, and their isomers, lower alkyl ethers, e.g.,diethyl ether, cyclic ethers, e.g. 1,4-dioxane, esters, e.g. ethylacetate, hydrocarbons, e.g. benzene, and mixtures thereof. Hydrogen##STR110## is employed at low pressures, e.g. atmospheric up to 30 psig.Temperatures in the range 10°-40° C. are useful.

In step (b) R₁₃ of compound LIV is replaced with hydrogen by hydrolysisin aqueous mixture containing water-miscible solvents such as ethanol,acetone, 1,4-dioxane, or tetrahydrofuran, in the presence of a base suchas sodium or potassium carbonate. The carbonate is used preferably inequivalent or slight excess of equivalent amounts. Temperatures in therange -10 to 100° C. are useful.

In step (c), representing several steps, diol XXXI is transformed tocompound LV by successively (1) blocking the two hydroxy groups withblocking groups within the scope of R₁₈ as defined above for Chart A,using the appropriate acid chloride or anhydride reagents and conditionsdescribed above; (2) converting the ##STR111## acetal moiety to analdehyde group by acid hydrolysis discussed for step (d) of Chart Aabove; and (3) transforming the aldehyde group to a moiety of theformula -CH═CR₃ G using a Wittig reaction as discussed for step (e) ofChart A above.

In step (d), compound LVI is obtained by deblocking if necessary. WhenC_(p) H_(2p) is a valence bond, and R₁₈ is a hindered carboxyacyl, e.g.t-butyl ##STR112## R₁₈ on the phenolic hydroxy is selectively replacedwith hydrogen by hydrolysis, preferably with the reagents employed forstep (b) of Chart D above, but using a temperature range of about -10°to 40° C. At higher temperatures there is some decrease in selectivity.

In step (e) a Williamson synthesis is employed to obtain compound LVII,using reagents discussed above for step (g) of Chart A. When R₁ inHal-CH₂ -COOR₁ is an ester group, the condensing base is preferably ahydride, e.g. sodium, lithium, potassium, or calcium hydride.

Intermediate LVII of Chart D is transformed to intermediate XXXV ofChart A and thence to final products XXXVI by methods disclosed hereinor known in the art.

For phenylene compounds, reference to Charts E and F will make clear thesteps by which starting material XXX is transformed to products LXXIIand LXXV. The formula-XXX compound has been described above for Chart A.

In Charts E and F the symbols Q, R₁, R₃, R₁₆, R₁₈, R₁₉, R₂₀, and havethe same meanings as for Charts A-D above.

Referring to Chart E, in step (a) oxetane LXIII is obtained by reactionof the formula-XXX bicyclic hexene with an aldehyde of the formula##STR113## wherein R₁₉ is hydrogen or alkyl of one to 4 carbon atoms,inclusive. Such aldehydes are available or readily prepared by methodsknown in the art. Chart G summarizes the steps employed herein (SeePreparations ##STR114## 2 - 6 for the preparation of(m-formylphenyl)propionate, methyl ester).

The conditions for the formation of oxetane LXIII are similar to thosedescribed above for step (a) of Chart B. Likewise steps (b) through (h)of Chart E to the formula-LXVIII alkene use conditions described abovefor steps (b) through (h) of Chart B or reactions which are known in theart. Subsequent steps by which the PGE-type products LXXII are obtainedare similar to and employ the same conditions as the corresponding stepsof Chart B. For this purpose a choice of three methods is given:hydrolysis of a bis(alkanesulfonic acid) ester, formolysis, or by way ofa cyclic ortho ester, the first being preferred.

Reference to Chart F will show the steps leading from a formula-LXXXIIIalkene, readily available from the formula-LXVIII alkene of Chart E, tothe PGF₁α -type products of formula LXXV.

The novel intermediates of Charts A, B, C, D, E, and F, including thosecompounds represented by formulas XX, XXI, XXII, XXIV, XXXI, XXXII,XXXIII, XXXV, XXXIV, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, XLIV,XLVI, XLVII, XLVIII, XLIX, LIV, LV, LVI, LVII, LXIII, LXIV, LXV, LXVI,LXVII, LXVIII, LXX, LXIX, LXXI, LXIII, and LXXIV are frequently notisolated but used directly for subsequent process step. When they areisolated, they are purified by methods known in the art, for examplepartition extraction, fractional crystalization, and, preferably, silicagel column chromatography.

The products represented by formulas XXXVI, XLV, L, LXXII, and LXXVobtained from these intermediates are often a mixture of 15-α and 15-βisomers. These are separated by methods known in the art, for example,by chromatography on neutral silica gel. In some instances, particularlywhere R₃ is alkyl, the lower alkyl esters are more easily separated thanare the corresponding acids. In those cases wherein R₁ is hydrogen, itis advantageous to esterify the mixture of acids, as with diazomethane,to form the methyl esters, separate the two epimers, and then, ifdesired, replace the carboxyl methyl with hydrogen by methods known inthe art.

When an optically active intermediate or starting material is employed,subsequent steps yield optically active intermediates or products. Thatoptical isomer of bicyclo hexene XXX is used which will yield productXXXVI, for example, in the configuration corresponding to that of thenaturally occurring prostaglandins. When the racemic form of theintermediate or starting material is employed, the subsequentintermediates or products are obtained in their racemic form.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention can be more fully understood by the time followingexamples and preparations:

All temperatures are in degrees centigrade.

Infrared absorption spectra are recorded on a Perkin-Elmer Model 421infrared spectrophotometer. Except when specified otherwise, undiluted(neat) samples are used.

NMR spectra are recorded on a Varian A-60, A-60D, or T-60spectrophotometer using deuterochloroform solutions withtetramethylsilane as an internal standard (downfield).

Mass spectra are recorded on a CEC Model 110B Double Focusing HighResolution Mass Spectrometer or an LKB Model 9000 Gas Chromatograph-MassSpectrometer (ionization voltage 70 ev).

Circular dichroism curves are recorded on a Carey 60 recordingspectropolarimeter.

Specific rotations are determined for solutions of a compound in thespecified solvent with a Perkin-Elmer Model 141 Automatic Polarimeter."Brine," herein, refers to an aqueous saturated sodium chloridesolution.

"Skellysolve-B" refers to mixed isomeric hexanes.

Silica gel chromatography, as used herein, is understood to includeelution, collection of fractions, and combination of those fractionsshown by TLC (thin layer chromatography) to contain the desired productfree of starting material and impurities.

PREPARATION 1 Optically ActiveBicyclo[3.1.9]-hex-2-ene-6-endo-carboxaldehyde

Following the procedure of Preparation 1 of U.S. Pat. No. 3,711,515,racemic bicyclo[3.1.0]hex-2-ene-6-endo-carboxaldehyde is prepared frombicyclo[2.2.1]hepta-2,5-diene and peracetic acid.

The racemic compound is resolved by the procedure of Example 13 of U.S.Pat. No. 3,711,515, forming an oxazolidine as follows.

Racemic bicyclo[3.1.0]hex-2end-6-endo-carboxaldehyde (12.3 g.) and1-ephedrine (16.5 g.) are dissolved in about 150 ml. of benzene. Thebenzene is removed under vacuum and the residue is taken up in about 150ml. of isopropyl ether. The solution is filtered, then cooled to -13° C.to yield crystals of2-endo-bicyclo[3.1.0]hex-2-en-6-yl-3,4-dimethyl-5-phenyl-oxazolidine,11.1 g., m.p. 90°-92° C. Three recrystallizations from isopropyl ether,cooling each time to about -2° C., yield crystals of the oxazolidine,2.2 g., m.p. 100°-103° C., now substantially a single isomeric form asshown by NMR.

The above re-crystallized oxazolidine (1.0 g.) is dissolved in a few ml.of dichloromethane, charged to a 20 g. silica, gel column and elutedwith dichloromethane. The silica gel is chromatography-grade (Merck),0.05-0.2 mm. particle size, with about 4-5 g. of water per 100 g.Fractions of the eluate are collected, and those shown by thin layerchromatography (TLC) to contain the desired compound are combined andevaporated to an oil (360 mg.). This oil is shown by NMR to be thedesired title compound, substantially free of the ephedrine, insubstantially a single optically-active isomeric form. Points on thecircular dichroism curve are (λ in nm.,θ): 350, 0; 322.5, -4,854; 312,-5,683; 302.5, -4,845; 269, 0; 250, 2,368; 240, 0; and 210, -34,600.

PREPARATION 2 m-(Bromomethyl)-benzylmalonate, Dimethyl Ester (FormulaLXXVII)

Refer to Chart G. A solution of dimethyl malonate (26.42 g.) in 600 ml.of tetrahydrofuran is treated with potassium tertiary butoxide (10.52g.) for 5 min. at about 25° C. Thereupon α,α'-dibromo-m-xylene (25.0 g.)is added and the mixture stirred at ambient temperature for 2.5 hr. Thereaction is quenched by addition of 100 ml. of water and 50 ml. of 5%hydrochloric acid. The mixture is extracted with diethyl ether and theextract is washed with water and brine, dried over magnesium sulfate andconcentrated to an oil. The crude product is subjected to chromatographyon silica gel, eluting with Skellysolve B-ethyl acetate (first 95:5 andthen 50:50). Yield of title compound: 31.5 g., having NMR peaks at 3.67,4.43, and 7.20 δ.

PREPARATION 3 m-(Acetoxymethyl)-benzylmalonate, Dimethyl Ester (FormulaLXXVIII)

Refer to Chart G. A mixture of m-(bromomethyl)-benzylmalonate, dimethylester (Preparation 2, 31.5 g.) and potassium acetate (17.5 g.) in 280ml. of dimethylformamide is heated at 50° C. for about 0.5 hr. until nostarting material is shown by TLC (thin layer chromatography on silicagel plates, in Skellysolve B-ethyl acetate (75:25). The mixture is takenup in diethyl ether-Skellysolve B (1:1) and washed with water and brine,dried over magnesium sulfate, and concentrated to an oil. The crudeproduct is subject to silica gel chromatography, eluting withSkellysolve B-ethyl acetate (90:10 to 30:70). Yield of title compound:9.66 g., having infrared absorption at 1740, 1610, 1595, 1490, 1435,1230, 1155, and 1030 cm⁻¹ ; NMR peaks at 2.08, 3.67, 5.07, and 7.19 δ;and mass spectral peaks at 294, 134, 101, 74, 59, 57, 45, 43, 42, 29,and 15.

PREPARATION 4 m-(Hydroxymethyl)-phenylpropionic Acid (Formula LXXIX)

Refer to Chart G. A solution of m-(acetoxymethyl)benzylmalonate,dimethyl ester (Preparation 3, 9.16 g.) in 45 ml. of dioxane is treatedwith 137 ml. of 10% sodium hydroxide at about 25° C. for 15 min. Themixture is acidified to pH 1.0 with sulfuric acid, treated with anadditional 3 ml. of sulfuric acid and heated at reflux for about 36 hr.The mixture is cooled, diluted with 430 ml. brine and extracted withchloroform. The extract is washed with brine, dried over magnesiumsulfate, and concentrated. Yield of title compound: 4.31 g., having NMRpeaks at 2.40-3.18, 4.58, 7.17, and 7.53δ.

PREPARATION 5 m-(Hydroxymethyl)-phenylpropionate, Methyl Ester (FormulaLXXX, wherein R₁₉ is methyl)

Refer to Chart G. A solution of m-(hydroxymethyl)-phenylpropionic acid(Preparation 4, 4.31 g.) in 7.15 ml. of dichloromethane is treated with2.29 g. of methanol and 0.076 ml. of concentrated sulfuric acid, heatedat reflux for 3.0 hr. The mixture is cooled, diluted with brine, andextracted with diethyl ether. The extract is washed with sodiumbicarbonate solution and brine, dried over magnesium sulfate, andconcentrated to an oil. Yield of title compound: 3.31 g. On subjectingthe product to silica gel chromatography, eluting with SkellysolveB-ethyl acetate (75:25 to 35:65), there is recovered 95% of the productin selected fractions, having NMR peaks at 2.37- 3.17, 3.60, 4.58, and7.15 δ.

PREPARATION 6 (m-Formylphenyl)propionate, Methyl Ester (Formula LXXXI,wherein R₁₉ is methyl)

Refer to Chart G. A mixture of m-(hydroxymethyl)-phenylpropionate,methyl ester (Preparation 5, 3.72 g.) and 40.92 ml. of 1M. cericammonium nitrate solution in 40.92 ml. of acetic acid is stirred at 65°C. for 2 hr. Then another 2 ml. of ceric ammonium nitrate solution isadded and treatment continued at 65° C. for one hr. The mixture iscooled, diluted with brine and extracted with diethyl ether. The etherextract is washed with brine and water, dried over sodium sulfate, andconcentrated to an oil.

The above product, containing the acid, is converted to the titlecompound with diazomethane. The mixture is quenched with 10% aceticacid, diluted with brine, and extracted with diethyl ether. The etherextract is washed with sodium bicarbonate solution and brine, dried, andconcentrated to the title compound, 2.90 g. Taking additional material,the combined lot (4.48 g.) is subjected to silica gel chromatography,eluting with Skellysolve B-ethyl acetate (90:10 to 60:40) to yield 3.532g., b.p. 0.35 mm. 105°-107° C. and having NMR peaks at 2.50-3.28, 3.65,7.17-7.93, and 10.00 δ; mass spectral peaks at 192, 161, 133, 132, 131,119, 105, 103, 77 and 51; and infrared absorption bands at 3000, 2940,2840, 2720, 1735, 1700, 1605, 1585, 1485, 1435, 1295, 1240, 1200, 1160,1145, 795, 690, and 650 cm⁻¹ ; and R_(f) 0.36 (TLC on silica gel in 25%ethyl acetate-Skellysolve B).

EXAMPLE 1 1-Bicyclo[3.1.0]hex-2-ene-6-endocarboxaldehyde NeopentylGlycol Acetal (Formula XXX: R₅ and R₆ taken together are --CH₂ -C(CH₃)₂-CH₂ -- and is endo).

A mixture of 2,2-dimethyl-1,3-propanediol (900 g.). 5 l. of benzene and3 ml. of 85% phosphoric acid is heated at reflux. To it is added, in 1.5hr., a solution of optically activebicyclo[3.1.0]hex-2-ene-6-endo-carboxaldehyde (Prep. 1, 500 g.) in oneliter of benzene. Provision is made to take off azeotropically distilledwater with a Dean-Stark trap. After 3 hr. the mixture is cooled andextracted with 2 liters of 5% sodium bicarbonate. The organic phase isdried over sodium sulfate and concentrated under reduced pressure. Theresulting semisolid residue is taken up in methanol and recrystallized,using a total of 1200 ml. of methanol to which 600 ml. of water isadded, then chilled to -13° C. to yield 300 g. of the title compound,m.p. 52°-55° C., and having NMR peaks at 0.66, 1.20, 0.83-2.65,3.17-3.8, 3.96, and 5.47-5.88 δ, [α]_(D) - 227° (C═0.8976 in methanol),and R_(f) 0.60 (TLC on silica gel in 25% ethyl acetate in mixed isomerichexanes). Further work-up of the mother liquors yields 50-100 g. ofadditional product.

Following the procedures of Example 1 but replacing the aldehyde withoptically active bicyclo[3.1.0]hex-2-ene-6-exo-carboxaldehyde (see U.S.Pat. No. 3,711,515), there is obtained the corresponding formula-XXXacetal.

Following the procedures of Example 1 but using either the endo or exoform of the aldehyde and substituting for 2,2-dimethyl-1,3-propanediolone of the following glycols: ethylene glycol, 1,2-propanediol,1,2-hexanediol, 1,3-butanediol, 2,3-pentanediol, 2,4-hexanediol,2,4-octanediol, 3,5-nonanediol, 3,3-dimethyl-2,4-heptanediol,4-ethyl-4-methyl-3,5-heptanediol, phenyl-1,2-ethanediol and1-pentyl-1,2-propanediol, there are obtained the correspondingformula-XXX acetals.

EXAMPLE 2 d-8-(m-Acetoxyphenyl)-7-oxa-tricyclo[4.2.0.0²,4]octane-6-endo-carboxaldehyde Neopentyl Glycol Acetal (Formula XX: C_(p)H_(2p) is a valence bond with attachment in the meta position, R₅ and R₆taken together are --CH₂ -C(CH₃)₂ -CH₂ --, R₁₃ is ##STR115## and isendo).

Refer to Chart A, step (d). A solution of the formula-XXX1-bicyclo[3.1.0]hex-2-ene-6-endo-carboxaldehyde neopentyl glycol acetal(Example 1, 5.82 g.) and m-acetoxybenzaldehyde (1.64 g.) in 25 ml. ofbenzene is charged to a Pyrex photolysis vessel equipped with animmersible water-cooled cold-finger and a fritted gas inlet tube.Dissolved oxygen is removed by bubbling nitrogen through the solution.The mixture is then irradiated at 350 nm. with a Rayonet Type RSPreparative Photochemical Reactor (The Southern New England UltravioletCo., Middletown, Conn.) equipped with six RUL 3500 A lamps. After 24 hr.the photolysate is concentrated under reduced pressure to a pale yellowoil, 10 g., which is subjected to silica gel chromatography. Elutionwith 10-70% ethyl acetate in Skellysolve B (mixture of isomeric hexanes)yields separate fractions of the recovered starting materials and theformula-XX title compound, a pale yellow oil, 0.86 g., having NMR peaksat 0.68, 1.20, 0.8-2.5, 2.28, 2.99, 3.12-3.88, 3.48, 4.97-5.52, and6.78-7.60 δ; infrared absorption bands at 3040, 2950, 2860, 2840, 1765,1610, 1590, 1485, 1470, 1370, 1205, 1115, 1020, 1005, 990, 790. and 700⁻¹, mass spectral peaks at 358, 357, 116, 115, 108, 107, 79, 70, 69, 45,43, and 41; [α]_(D) +55° (C═0.7505 in 95% ethanol); and R.sub. f 0.18(TLC on silica gel in 25% ethyl acetate in mixed isomeric hexanes).

Following the procedures of Example 2 but replacing the formula-XXXacetal with the formula-XXX compounds disclosed following Example 1,there are obtained the corresponding formula-XX compounds in their endoor exo forms and with corresponding exemplification of R₅ and R₆.

Likewise following the procedures of Example 2 but replacingm-acetoxybenzaldehyde with aldehydes within the scope of formula XXVIabove, as to C_(p) H_(2p), the attachment position on the phenyl ring,and the carboxyacyl group R₁₃, or defined above, the correspondingformula-XX oxetanes are obtained wherein is endo or exo, and R₅ and R₆correspond to the glycols employed after Example 1 above. Specifically,the following formula-XXVI aldehydes are employed: ##STR116##

EXAMPLE 3d-2-Exo-[m-(pivaloyloxy)benzyl]-3-exo-(pivaloyloxy)-bicyclo[3.1.0]hexane-6-endo-carboxaldehydeNeopentyl Glycol Acetal (Formula XXXII: C_(p) H_(2p) is a valence bondwith attachment in the meta position, R₅ and R₆ taken together are --CH₂-C(CH₃)₂ --CH₂ -, R₁₈ is ##STR117## and is endo).

I. Refer to Chart A, steps (b) and (c). A mixture of lithium (0.25 g.)in 70 ml. of ethylamine is prepared at 0° C. and cooled to -78° C. Asolution of the formula-XXd-8-(m-acetoxyphenyl)-7-oxa-tricyclo[4.2.0.0²,4]-octane-6-endo-carboxaldehyde neopentyl glycol acetal (Example 2, 1.83g.) in 10 ml. of tetrahydrofuran is added dropwise in about 5 min. Afterstirring at -78 ° C. for about 3.5 hr. the reaction is quenched withsolid ammonium chloride and water-tetrahydrofuran. Unreacted lithium isremoved, the mixture is warmed slowly to about 25° C., and ethylamine isremoved. The residue is neutralized with dilute acetic acid, mixed with200 ml. of brine, and extracted with ethyl acetate. The organic phase iswashed with brine and a mixture of brine and saturated aqueous sodiumbicarbonate (1:1), and dried over sodium sulfate. Concentration underreduced pressure yields the formula-XXXI diol as a pale tan foamed oil,1.64 g., having R_(f) 0.03 (TLC on silica gel in 25% ethyl acetate inmixed isomeric hexanes).

II. The product of part (I) is dissolved in 30 ml. of pyridine andtreated with 1.5 ml. of pivaloyl chloride over a period of 22 hr. atabout 25° C. The reaction mixture is mixed with water, then brine andextracted with ethyl acetate. The organic phase is washed successivelywith brine, water, saturated aqueous copper (II) sulfate, saturatedaqueous sodium bicarbonate, and brine, and dried over sodium sulfate.Concentration under reduced pressure yields a residue, 2.53 g., which issubjected to silica gel chromatography to yield the formula-XXXII titlecompound, 1.87 g., having NMR peaks at 0.71, 1.20, 1.33, 0.9-3.1,3.28-4.00, 4.17, 4.7-5.2, and 6.77-7.53 δ; mass spectral peaks at 486,485, 115, 73, 72, 57, 44, 43, 42, 41, 30, 29, 15; [α]_(D) +19° (C═0.9340 in ethanol); R_(f) 0.50 (TLC on silica gel in 25% ethyl acetatein mixed isomeric hexanes); and m.p. 107.1-112.2° C.

EXAMPLE 4 d-2-Exo-(m-acetoxybenzyl)-3-exo-acetoxybicyclo[3.1.0]hexane-6-endo-carboxaldehydeNeopentyl Glycol Acetal (Formula XXXII: C_(p) H_(2p) is a valence bondwith attachment in the meta position, R₅ and R₆ taken together are --CH₂-C(CH₃)₂ -CH₂ --, R₁₈ is ##STR118## and is endo).

Following the procedures of Example 3-(II) but replacing pivaloylchloride with acetic anhydride, and using 1.01 g. of the formula-XXXIdiol, there is obtained the title compound, 0.75 g., having NMR peaks at0.72, 1.22, 1.98, 2.27, 0.8-3.0, 3.28-3.85, 4.17, 4.75-5.22, and6.8-7.47 δ; mass spectral peaks at 402, 401, 115, 107, 73, 69, 45, 44,43, 42, 41, 30; [α]_(D) +7° (C═0.7060 in ethanol); and R_(f) 0.66 (TLCon silica gel in 50% ethyl acetate in mixed isomeric hexanes).

EXAMPLE 52-Exo-[m-(pivaloyloxy)benzyl]-3-exo-(pivaloyloxy)bicyclo[3.1.0]hexane-6-endo-carboxaldehyde(Formula XXI: C_(p) H_(2p) is a valence bond with attachment in the metaposition, R₁₆ is ##STR119## and is endo).

Refer to Chart A, step (d). The formula-XXXII acetal, i.e.d-2-exo-[m-(pivaloyloxy)benzyl]-3-exo-(pivaloyloxy)-bicyclo[3.1.0]hexane-6-endo-carboxaldehydeneopentyl glycol acetal (Example 3, 0.48 g.) is treated at 0° C. with 25ml. of 88% formic acid for 4 hr. The mixture is diluted with 200 ml. ofbrine and extracted with ethyl acetate. The organic phase is washed withbrine and saturated aqueous sodium bicarbonate, and dried over magnesiumsulfate. Concentration under reduced pressure yields an oil, 0.55 g.,which is subjected to silica gel chromatography. Elution with 5-15%ethyl acetate in Skellysolve B yields the formula-XXI title compound asan oil, 0.37 g., having NMR peaks at 1.20, 1.33, 0.6-3.2, 5.1-5.5,6.6-7.5, and 9.73 δ; and R_(f) 0.50 (TLC on silica gel in 25% ethylacetate in mixed isomeric hexanes).

EXAMPLE 62-Exo-[m-(pivaloyloxy)benzyl]-3-exo-(pivaloyloxy)-6-endo-(cis-1-heptenyl)bicyclo[3.1.0]hexane(Formula XXII: C_(p) H_(2p) is a valence bond with attachment in themeta position, G is n-pentyl, R₁₆ is ##STR120## R₃ is hydrogen, and isendo); and2-Exo-(m-hydroxybenzyl)-(3-exo-hydroxy-6-endo-(cis-1-heptenyl)bicyclo[3.1.0]hexane(Formula XXXIII: C_(p) H_(2p) is a valence bond in the meta position, Gis n-pentyl, R₃ and R₁₆ are hydrogen, and is endo).

I. Refer to Chart A, steps (e) and (f). The Wittig ylid reagent isprepared in 10 ml. of benzene from n-hexyltriphenylphosphonium bromide(0.79 g.) and n-butyllithium (0.6 ml. of 2.32 M. solution in hexane) atabout 25° C. for 0.5 hr. After the precipitated lithium bromide hassettled, the solution is removed and added to a cold (0° C.) slurry ofthe formula-XXI aldehyde (Examples 5, 0.37 g.). After 15 min. there isadded 1.0 ml. of acetone and the mixture is heated to 60° C. for 10 min.The mixture is concentrated under reduced pressure. The residue iswashed with 10% ethyl acetate in Skellysolve B and these washings areconcentrated to the formula-XXII title compound, an oil, 0.33 g. havingNMR peaks at 1.18, 1.33, 0.6- 3.2, 4.5-6.0 and 6.67- 7.62 δ; and R_(f)0.78 (TLC on silica gel in 25% ethyl acetate in Skellysolve B).

II. The above product of part (I) is transformed to the formula-XXXIIIdiol by treatment with sodium methoxide (2.5 ml. of a 25% solution inmethanol) for 4 hrs., followed by addition of 0.5 g. of solid sodiummethoxide and further stirring for 15 hr. at 25° C., then at reflux for6 hr. The mixture is cooled, mixed with 300 ml. of brine, and extractedwith ethyl acetate. The organic phase is washed with brine, dried overmagnesium sulfate, and concentrated under reduced pressure to a residue,0.27 g. The residue is subjected to silica gel chromatography, elutingwith 25-35% ethyl acetate in Skellysolve B, to yield the formula-XXXIIItitle compound as an oil, 0.21 g., having NMR peaks at 0.87, 0.6-3.25,3.88-4.35, 4.82-5.92, and 6.47-7.33 δ; and R_(f) 0.13 (TLC on silica gelin 25% ethyl) acetate in Skellysolve B).

Following the procedures of Examples 3, 5, and 6 but replacing theformula XX oxetane with each of those obtained following Example 2,there are obtained successively the corresponding formula-XXXI, --XXXII,--XXI, and --XXII compounds wherein C_(p) H_(2p) and its attachmentposition on the phenyl ring correspond to the specific aldehydesemployed following Example 2. These are obtained in both their endo andexo forms.

Further following the procedures of Example 6, but replacing the Wittigylid reagent with one prepared from a compound of the formula

    Br-P(C.sub.6 H.sub.5).sub.3 -CHR.sub.3 -G

wherein --CHR₃ -G is each of the following:

--(CH₂)₃ -CH₃

--(ch₂)₄ -ch₃

--(ch₂)₆ -ch₃

--(ch₂)₇ -ch₃

--ch(ch₃)-(ch₂)₅ -ch₃

--ch₂ -ch(ch₃)-(ch₂)₃ -ch₃

--ch₂ -c(ch₃)₂ -(ch₂)₃ -ch₃

--ch(ch₃)-c(c₂ h₅)₂ -(ch₂)₃ -ch₃

--ch₂ -chf-(ch₂)₃ -ch₃

--ch₂ -cf₂ -(ch₂)₃ -ch₃

--ch(ch₃)-cf₂ -(ch₂)₃ -ch₃ ##STR121## --(ch₂)₂ -c.tbd.c-c₂ h₅ --ch₂-ch(ch₃)-c.tbd.c-c₂ h₅

--ch₂ -c(ch₃)₂ -c.tbd.c-c₂ h₅

or

--CH(CH₃)-CH₂ -C.tbd.C-C₂ H₅

there are obtained the corresponding compounds within the scope offormula XXII wherein C_(p) H_(2p) and its attachment to the phenyl ringcorrespond to the specific compounds of Example 6 and those illustratedin the paragraph immediately thereafter, in both their endo and exoforms.

EXAMPLE 72-Exo-{m-[(carboxy)methoxy]}-3-exo-hydroxy-6-endo-(cis-1-heptenyl)bicyclo[3.1.0]hexane(Formula XXXIV: C_(p) H_(2p) is a valence bond with attachment in themeta position, G is n-pentyl, R₁, R₃, and R₁₆ are hydrogen, and isendo).

Refer to Chart A, step (g). The formula-XXXIII diol, i.e.2-exo-(m-hydroxybenzyl)-3-exo-hydroxy-6-endo-(cis-1hepentyl)bicyclo[3.1.0]hexane(Example 6, 0.19 g.) is treated in 8 ml. of dioxane with bromoaceticacid (0.61 g.) and 6 ml. of 1N. aqueous sodium hydroxide. After themixture has been heated at reflux for 3 hr., with sodium hydroxidesolution added when necessary to maintain a pH of about 10, the mixtureis cooled, diluted with 100 ml. of water, and extracted with diethylether. The aqueous phase is acidified to pH 1-2 and extracted with ethylacetate to yield the formula-XXXIV title compound, a pale yellow oil,0.20 g. Recovered formula-XXXIII diol is obtained from the diethyl etherorganic phase on drying and concentrating, 0.025 g.

EXAMPLE 8 3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁α (Formula VIII:C_(p) H_(2p) is a valence bond with attachment in the meta position, R₂is n-pentyl, and R₁ and R₃ are hydrogen).

I. Refer to Chart A. The formula-XXXIV alkene is transformed to thetitle compound applying the procedures disclosed in U.S. Pat. No.3,711,515. Thus, compound XXXIV (Example 7) is hydroxylated by theprocedures of Example 6 of that patent to the formula-XXXV glycol ofChart A, using osmium tetroxide either alone or in combination withN-methylmorpholine oxide-hydrogen peroxide complex.

The glycol is then either (1) sulfonated, for example to yield thebismesylate, and then hydroyzed to a mixture of the title compound andits 15-epimer, applying the procedures of Example 7 of that patent, or(2) treated with substantially 100% formic acid to form the diformate ofVIII and thereafter hydroyzed to a mixture of the title compound and its15 epimer, applying the procedures of Examples 20 and 21 of that patent.The epimers are separated by silica gel chromatography to yield thetitle compound and its 15-epimer.

II. A third route from glycol XXXV to the title compound is by way of acyclic ortho ester ##STR122## wherein C_(p) H_(2p), R₂₄, R₂₅ and are asdefined above. The glycol XXXV is treated as a 1-20% solution in benzenewith trimethyl orthoformate (1.5-10 molar equivalents) and a catalyticamount (1% of the weight of the glycol) of pyridine hydrochloride atabout 25° C. The reaction is followed by TLC (thin layer chromatography)and is complete in a few minutes. There is thus obtained the formula-LIcyclic ortho ester in 100% yield.

The cyclic ortho ester is then treated with 20 volumes of 100% formicacid at about 25° C. In about 10 min. the reaction mixture is quenchedin water or aqueous alkaline bicarbonate solution and extracted withdichloromethane. The organic phase is shaken with 5% aqueous sodiumbicarbonate, dried over sodium sulfate, and concentrated to yield theformula LII diester, in this example identical with the diformate ofcompound VIII. The diformate is contacted with 10-50 volumes ofanhydrous methanol and 10-20% of its weight of potassium carbonate atabout 25° C. until the formyl groups are removed. The mixture of15-epimers thus obtained is then separated to yield the formula VIIItitle compound and its 15-epimer.

Following the procedures of Example 8, each of the formula-XXXIV alkenesdisclosed following Example 7 is converted into the correspondingphenylene-oxa PGF.sub.α analog and its 15-epimer. There are likewiseformed the corresponding phenylene oxa 17,18-didehydro-PGF.sub.α analogsas shown in Chart C.

EXAMPLE 9 2-Exo-[m-(carboxmethoxy)benzyl]-3-exohydroxy-6-endo-(cis-1-heptenyl)bicyclo[3.1.0]hexane(Formula XLII: C_(p) H_(2p) is a valence bond with attachment in themeta position, G is n-pentyl, R₁ and R₃ are hydrogen, and is endo).

Refer to Chart B, steps (a)-(f). There is first prepared theformula-XXXVII oxetane. Following the procedures of Examples 1 and 2,but replacing the m-acetoxybenzaldehyde of Example 2 with an aldehydewithin the scope of ##STR123## as to C_(p) H_(2p), the attachmentposition on the phenyl ring, and the carboxyl group R₁₉, as definedabove, the corresponding formula XXXVII oxetanes are obtained with afully developed side chain. Specifically, the following formula-LIIIaldehydes are employed: ##STR124##

Thereafter, following the procedures of Examples 3, 5, and 6, butreplacing the formula-XX ocetane of Example 3 with those obtained by theprocedure disclosed in the above paragraph of this example, there areobtained the corresponding formula-XLI products. Likewise followingthose procedures of Examples 3, 5, and 6 but replacing the Wittig ylidreagent of Example 6 with each one disclosed after Example 6, andapplying it to each of the above formula-XX compounds of this example,there are obtained the corresponding formula-XLI compounds with thosespecific side-chains.

Finally, the blocking group on each XLI compound are removed by methodsdisclosed herein or known in the art to yield the formula-XLII titlecompound and the corresponding formula-XLII compounds from thoseformula-XLI compounds above.

EXAMPLE 10 2-Exo-{m-[(methoxycarbonyl)methoxy]benzyl}-3-exohydroxy-6-endo-(cis-1-heptenyl)bicyclo[3.1.0]hexane (Formula XLII: C_(p)H_(2p) is a valence bond with attachment in the meta position, G isn-pentyl, R₁ is methyl, R₃ is hydrogen, and is endo).

Refer to Chart B. The formula-XLII acid (Example 7, 0.20 g.) is treatedin methanol solution at 0° C. with a solution of diazomethane in diethylether (prepared from N-methyl-N-nitroso-N'-nitroguanidine (2.0 g.) andpotassium hydroxide (6 ml. of 40% aqueous solution)) until a permanentyellow color is produced, and the mixture is concentrated to yield thetitle compound, a pale tan oil.

EXAMPLE 11l-6-Endo-(cis-1-heptenyl)-2-exo-{m-[(methoxycarbonyl)methoxy]benzyl}bicyclo[3.1.0]hexan-3-one(Formula XLIII: C_(p) H_(2p) is a valence bond with attachment in themeta position, G is n-pentyl, R₁ is methyl, R₃ is hydrogen, and isendo).

Refer to Chart B, step (g). The formula-XLII methyl ester is oxidized tothe bicyclic hexanone as follows. The formula-XLII methyl ester (example8, 0.21 g.) is added in 2 ml. of dichloromethane to a solution ofCollins reagent (prepared from pyridine (0.53 g.) and chromium trioxide(0.34 g.) in 10 ml. of dichloromethane) at about 25° C. for 15 min. Themixture is then shaken with a mixture of 60 ml. of diethyl ether, ice,and 25 ml. of 1 N. aqueous sodium hydroxide, and the organic phase isseparated. The organic phase is washed with 1 N. aqueous sodiumhydroxide, 1.2 N. aqueous hydrochloric acid, and brine, dried, andconcentrated under reduced pressure. The residue, a colorless oil, 0.19g., is subjected to silica gel chromatography, eluting with 5-20% ethylacetate in Skellysolve B. There is thus obtained the formula-XLIII titlecompound, a colorless oil, 0.13 g., having NMR peaks at 0.87, 0.6-3.3,3.77, 4.60, 4.5-5.1, 5.37-5.95, and 6.58- 7.40 δ; [α]_(D) -39° (C═0.8380in 95% ethanol); and R_(f) 0.42 (TLC on silica gel in 25% ethyl acetatein Skellysolve B).

Following the procedures of Examples 10 and 11, each of theabove-identified formula-XLII compounds following Example 9 is oxidizedto the corresponding formula-XLIII compound.

EXAMPLE 12 3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁, Methyl Ester(Formula IV: C_(p) H_(2p) is a valence bond with attachment in the metaposition, R₁ is methyl, R₂ is n-pentyl, and R₃ is hydrogen).

Following the procedures of Example 8, the formula-XLIII alkene istransformed in several steps to the title compound.

Likewise, following the same procedures, each of the formula-XLIIIalkenes disclosed following Example 11 is converted into thecorresponding phenylene-oxa PGE analog and its 15-epimer.

Following the procedures of Examples 1-12, each of the endointermediates is replaced by the corresponding exo intermediate to yieldthe corresponding exo intermediate or the ultimate phenylene-oxa PGanalog.

Likewise following the procedures of Examples 1-12, each of theoptically active isomers is replaced by the corresponding racemicmixture to yield the corresponding racemic intermediate or ultimatephenylene-oxa PG analog.

EXAMPLE 13d-2-Exo-(m-acetoxybenzoyl)-3-exo-hydroxybicyclo[3.1.0]hexane-6-endo-carboxaldehydeNeopentyl Glycol Acetal (Formula LIV: C_(p) H_(2p) is a valence bondwith attachment in the meta position, R₅ and R₆ taken together are --CH₂-C(CH₃)₂ -CH₂ -, R₁₃ is acetyl, and is endo).

Refer to Chart D, step (d). A mixture of the formula-XXd-8-(m-acetoxyphenyl)-7-oxa-tricyclo[4.2.0.0²,4]octane-6-endo-carboxaldehyde neopentyl glycol acetal (Example 2, 0.36g.), 10 ml. of ethyl acetate, 5 ml. of absolute ethanol, and 0.25 g. of10% palladium-on-carbon is shaken with hydrogen at one atmosphericpressure until one equivalent of hydrogen is consumed. The mixture isfiltered and the filtrate concentrated under reduced pressure to yieldthe title compound, 0.36 g. An analytical sample is obtained bysubjecting the product to silica gel chromatography: m.p. 122.2°-125.9°C.; [α]_(D) ²⁵ +31° (C. 0.9188 in ethanol); R_(f) 0.22 (TLC on silicagel in ethyl acetate-mixed isomeric hexanes (1:1)); NMR peaks at 0.72,1.23, 2.28, 3.23-3.83, 3.98-4.35, and 6.73-7.48 δ; and mass spectralpeaks at 360, 256, 214, 211, 125, 115, 108, 107, 69, 45, 43, and 41.

EXAMPLE 14d-2-Exo-[m-pivaloyloxy)benzyl]-3-exo(pivaloyloxy)-bicyclo[3.1.0]hexane-6-endo-carboxaldehyde Neopentyl Glycol Acetal (Formula XXXII:C_(p) H_(2p) is a valence bond with attachment in the meta position, R₅and R₆ taken together are --CH₂ -C(CH₃)₂ -CH₂ --, R₁₈ is ##STR125## andis endo).

Refer to Chart A, step (c).

I. There is first prepared the formula-XXI diol, namely2-exo-(m-hydroxybenzyl)-3-exo-hydroxy-bicyclo-[3.1.0]-hexane-6-endo-carboxaldehydeneopentyl glycol acetal. A solution of the formula LIV product ofExample 13 (17.97 g.) in 200 ml. of methanol is treated with a solutionof potassium carbonate (6.0 g.) in 65 ml. of water at 25° C. for 1 hr.The mixture is then concentrated under reduced pressure, diluted with500 ml. of ice and water, and acidified to pH 5-6 with 1M. aqueouspotassium hydrogen sulfate. The solution is saturated with sodiumchloride and extracted with 800 ml. of chloroform. The organic phase iswashed with brine, dried over sodium sulfate, and concentrated underreduced pressure to give the formula-XXXI diol, 17.83 g.

II. A solution of the above diol (17.83 g.) in 150 ml. of pyridine istreated with pivaloyl chloride (17.75 ml.) following the procedure ofExample 3-(II) to yield the title compound, 17.92 g., having the sameproperties as reported above.

EXAMPLE 152-Exo-{m[(carbomethoxy)methoxy]benzyl}-3-exo-(pivaloyloxy)-6-endo-(cis-1-heptenyl)bicyclo[3.1.0]hexane(Formula LVII: C_(p) H_(2p) is a valence bond with attachment in themeta position, G is pentyl, R₁ is methyl, R₃ is hydrogen, R₁₆ is##STR126## and is endo).

Refer to Chart D, steps (d) and (e).

I. There is first prepared the formula-LVI compound, namely2-exo-(m-hydroxybenzyl)-3-exo-(pivaloyloxy)-6-endo-(cis-1-heptenyl)-bicyclo[3.1.0]hexane.A solution of the formula-LV (XXII of Chart A) compound, namely2-exo-[m(pivaloyloxy)benzyl]-3-exo-(pivaloyloxy)-6-endo-(cis-1-heptenyl)-bicyclo[3.1.0]hexane(Example 6-(I), 1.42 g.) in 30 ml. of methanol and 2 ml. of water istreated with potassium carbonate (1.0 g.) at 25° C. for 3.5 hr. Themixture is concentrated under reduced pressure, diluted with 100 ml. ofsaturated aqueous potassium hydrogen sulfate and extracted with ethylacetate. The organic phase is washed with brine, dried over sodiumsulfate, and concentrated to give the formula-LVI compound, 1.20 g.having R_(f) 0.69 (TLC on silica gel in 25% ethyl acetate in isomerichexanes).

II. A solution of the above formula-LVI compound, 1.20 g., in 10 ml. of1,2-dimethoxyethane and treated with methyl bromoacetate (0.72 g.) and0.15 g. of 57% sodium hydride dispersion. After standing 1.5 hr. at 25°C., the mixture is diluted with 180 ml. of 1.2 N. aqueous hydrochloricacid and extracted with ethyl acetate. The organic phase is washed withbrine, dried over sodium sulfate and concentrated to give theformula-LVII title compound, 1.57 g. An analytical sample is obtained bysubjecting the product to silica gel chromatography: R_(f) 0.27 (TLC onsilica gel in 10% ethyl acetate in isomeric hexanes); NMR peaks at 0.87,1.18, 3.72, 4.55, 4.48-5.88, and 6.50-7.38 δ.

Following the procedures of Example 15(II) but replacing methylbromoacetate with a haloacetate within the scope of

Cl-CH₂ -COOCH₃

Br-CH₂ -COOC₂ H₅

Cl-CH₂ -COOC₈ H₁₇ (n)

l-CH₂ -COOCH₂ C₆ H₅

Cl-CH₂ -COO(m-Cl-C₆ H₄)

there are obtained the corresponding formula-LVII compounds wherein R₁is respectively methyl, ethyl, n-octyl, benzyl, and m-chlorophenyl.

Likewise following the procedures of Example 15(II) with each of theformula-LV (XXII of Chart A) compounds disclosed following Example 6 andusing each of the haloacetates specifically identified above, there areobtained the corresponding formula-LVII compounds.

EXAMPLE 16 dl-8-(m-[2-(Methoxycarbonyl)ethyl)phenyl]-7-oxa-tricyclo[4.2.0.0²,4 ]octane-6-endo-carboxaldehyde NeopentylGlycol Acetal (Formula LXIII wherein R₅ and R₆ taken together are --CH₂-C(CH₃)₂ -CH₂ -, R₁₀ is methyl, and is endo).

Refer to Chart E, step (a). A solution of racemicbicyclo(3.1.0)hex-2-ene-6-endo-carboxaldehyde neopentyl glycol acetal(corresponding to the optically active formula-XXX compound of Example1, 5.82 g.) and the formula-LXXXI (m-formylphenyl)propionate, methylester (Preparation 6, 0.96 g.) in sufficient benzene to bring to avolume of 30 ml. is charged to a Pyrex photolysis vessel equipped withan immersible water-cooled cold-finger and fritted gas inlet tube.Dissolved oxygen is removed by bubbling nitrogen through the solution.The mixture is then irradiated at 350 nm. with a Rayonet Type RsPreparative Photochemical Reacter (The Southern New England UltravioletCo., Middletown, Conn.) equipped with six RUL 3500 A lamps. After 17 hr.the photolysate is concentrated under reduced pressure to an oil, whichis subjected to silica gel chromatography. Elution with 10- 75% ethylacetate in Skellysolve B (mixture of isomeric hexanes) and finally ethylacetate yields separate fractions of the recovered starting materialsand the formula-LXIII title compound, an oil, 0.73 g., having NMR peaksat 0.67, 1.18, 3.65, 4.97- 5.55, and 6.93- 7.57 δ; mass spectral peaksat 386, 385, 115, 108, 84, 79, 69, 59, 45, 43, 41, and 29; infraredabsorption bands at 3020, 2940, 2860, 1735, 1605, 1590, 1470, 1435,1395, 1360, 1290, 1230, 1195, 1160, 1110, 1060, 1020, 1005, 985, 930,915, 835, 785 and 705 cm⁻¹ ; and R_(f) 0.18 (TLC on silica gel in ethylacetate-Skellysolve B(25:75)).

EXAMPLE 17dl-2-Exo-{m-[2-(methoxycarbonyl)ethyl]benzyl}-3-exo-(pivaloyloxy)-bicyclo[3.1.00]hexane-6-endo-carboxaldehydeNeopentyl Glycol Acetal (Formula LXV wherein R₅ and R₆ taken togetherare -CH₂ -C(CH₃)₂ -CH₂ -, R₁₆ is pivaloyl, R₁₉ is methyl and is endo).

I. Refer to Chart E, steps (b) and (c). A mixture of the formula-LXIIIoxetane (Example 16, 0.36 g., previously stirred with Raney Nickelcatalyst and filtered), 10 ml. of ethyl acetate, 5 ml. of ethanol, and0.25 g. of 10% palladium on charcoal is subjected to hydrogenation atone atmosphere at 25° C. until one molar equivalent has been absorbed.The mixture is filtered and concentrated to the formula LXVI compound, acolorless oil having R_(f) 0.29 (TLC on silica gel plate in ethylacetate-Skellysolve B (50:50)).

II. The product of part (I) is dissolved in 10 ml. of pyridine andtreated with 0.35 ml. of pivaloyl chloride for 2 days at about 25° C.The reaction mixture is mixed with 100 ml. of water, 200 ml. of diethylether, and saturated aqueous copper (II) sulfate. The ether extract iswashed with water, saturated aqueous sodium bicarbonate, and brine, anddried over magnesium sulfate. Concentration under reduced pressureyields an oil, 0.56 g., which after silica gel chromatography (elutingwith first dichloromethane and then ethyl acetate-Skellysolve B (35:65))yields the title compound as an oil, 0.48 g., having R_(f) 0.42 (TLC onsilica gel in ethyl acetate-Skellysolve B (25:75)); and NMR peaks at0.72, 1.21, 3.65, 4.18 (doublet, J = 6.5 Hz), 5.00 and 6.80- 7.40 δ.

EXAMPLE 18dl-2-Exo{m-[2-(methoxycarbonyl)ethyl]benzyl}-3-exo-(pivaloyloxy)bicyclo[3.1.0]hexane-6-endo-carboxaldehyde (Formula LXVII wherein R₁₆ ispivaloyl, R₂₀ is methyl, and is endo).

Refer to Chart E, step (d). The formula-LXV acetal, i.e.dl-2-exo-{m-[2-(methoxycarbonyl)ethyl]benzyl}-3-exo(pivaloyloxy)bicyclo[3.1.0]hexane-6-endo-carboxaldehydeneopentyl glycol acetal (Example 17, 0.48 g.) is treated at 0° C. with25 ml. of 88% formic acid for 2.75 hr. The mixture is diluted with 500ml. of brine, and extracted with 200 ml. of ethyl acetate. The organicphase is washed with brine and saturated aqueous sodium bicarbonate, anddried over sodium sulfate. Concentration under reduced pressure yieldsan oil, which when subjected to silica gel chromatography (eluting with10-30% ethyl acetate-Skellysolve B) yields the title compound as an oil,0.25 g. having NMR peaks at 1.22, 3.67, 5.15- 5.57, 6.87- 7.42, and 9.67δ (doublet, J = 4 Hz); and R_(f) 0.26 (TLC on silica gel in ethylacetate-Skellsolve B (25:75)).

EXAMPLE 19dl-2-Exo-{m-[2-(methoxycarbonyl)ethyl]benzyl}-3-exo-(pivaloyloxy)-6-endo(cis-1-heptenyl)bicyclo[3.1.0]hexane(Formula LXVIII, wherein R₃ is hydrogen, R₁₆ is pivaloyl, R₂₀ is methyl,and is endo).

Refer to Chart E step (e). The formula-LXVII aldehyde, i.e.dl-2-exo-{m-[2-(methoxycarbonyl)ethyl]benzyl}-3-exo(pivaloyloxy)bicyclo[3.1.0]hexane-6-endo-carboxaldehyde(Example 18, 0.25 g.) in 5 ml. of benzene is added to the Wittig ylidreagent (prepared in 15 ml. of benzene from n-hexyltriphenylphosphoniumbromide (0.60 g.) and n-butyllithium (0.52 ml. of 2.32 M. solution inhexane) at about 25° C. for 0.5 hr. and using the supernatant). After0.5 hr. there is added 1.0 ml. of acetone and the mixture stirred at 25°C. for 10 min. The mixture is diluted with 250 ml. of brine andextracted with 200 ml. of ethyl acetate. The organic phase is washedwith brine and dried over magnesium sulfate. Concentration under reducedpressure yields an oil, 0.54 g. which when subjected to silica gelchromatography (eluting with dichloromethane) yields the title compoundas an oil, 0.20 g. having R_(f) 0.66 (TLC on silica gel in 25 % ethylacetate-Skellysolve B) and NMR peaks at 0.88, 1.19, 1.25, 3.68, 4.68-6.03 and 6.86- 7.43 δ.

Thereafter, following the procedures of Chart F, the product of Example19 is converted to the racemic glycol corresponding to formula LXXIVwherein R₁ is methyl and thence todl-4,5,6-trinor-3,7-inter-m-phenylene-PGF₁α, methyl ester, correspondingto formula LXXV, a useful compound.

EXAMPLE 20dl-2-Exo-[m-(2-carboxyethyl)benzyl]-3-exo-hydroxy-6-endo-(cis-1-heptenyl)bicyclo[3.1.0]hexane(Formula LXIX wherein R₁ and R₃ are hydrogen, and is endo); anddl-2-Exo-{m-[2-(methoxycarbonyl)ethyl]benzyl}-3-exo-hydroxy-6-endo-(cis-1-heptenyl)-bicyclo[3.1.0]hexane(Formula LXIX wherein R₁ is methyl, R₃ is hydrogen, and is endo).

I. Refer to Chart E, step (f). The formula-LXVIII diester, i.e.dl-2-exo-{m-[2-(methoxycarbonyl)ethyl]benzyl}-3-exo-(pivaloyloxy)-6-endo-(cis-1-heptenyl)-bicyclo[3.1.0]hexane(Example 19, 0.20 g.) is treated in 5 ml. of methanol with 2.0 ml. of25% sodium methoxide in methanol at about 25° C. for 15 hr., then atreflux for 4 hr. The reaction mixture is acidified with 2 ml. of glacialacetic acid and then concentrated under reduced pressure. The residue istaken up in 200 ml. of ethyl acetate, washed with brine and dried oversodium sulfate. Concentration under reduced pressure yields theformula-LXIX title compound wherein R₁ is hydrogen as a pale yellow oil.

II. The product of step (I) above in methanol, is converted to themethyl ester with diazomethane at 25° C. for 3-5min. washed in ethylacetate solution with saturated aqueous sodium bicarbonate and brine anddried over sodium sulfate to the formula-LXIX title compound wherein R₁is methyl, an oil, 0.18 g. having R_(f) 0.20 (TLC on silica gel in 25%ethyl acetate-Skellysolve B).

EXAMPLE 21 dl-2-Exo-{m-[2-(methoxycarbonyl)ethyl]-benzyl}-6-endo-(cis-1-heptenyl)-bicyclo[3.1.0]hexane-3-one (FormulaLXX: R₁ is methyl, R₃ is hydrogen, and is endo).

Refer to Chart E, step (g). The formula-LXIX hydroxy compound, i.e.dl-2-exo-{m-[2-(methoxycarbonyl)ethyl]benzyl}3-exo-hydroxy-6-endo-(cis-1-heptenyl)-bicyclo[3.1.0]hexaneis oxidized as follows. The formula-LXIX compound wherein R₁ is methyl(Example 20, 0.18 g.) in dichloromethane is added to a solution ofCollins reagent (prepared from pyridine (0.48 g.) and chromium trioxide(0.3 g.) in 10 ml. dichloromethane at about 25° C. for 20 min.). Thereaction mixture is then shaken with a mixture of 100 ml. of diethylether and 300 ml. of brine. The organic phase is shaken with a mixtureof ice and 1N. aqueous sodium hydroxide, then washed with water,saturated aqueous copper (II) sulfate, water, and brine, and dried oversodium sulfate. Concentration under reduced pressure yields a paleyellow oil, 0.20 g., which when subjected to silica gel chromatography(eluting with 5- 10% ethyl acetate-Skellysolve B) yields the titlecompound, a colorless oil, 0.07 g., having R_(f) 0.61 (TLC on silica gelin 25% ethyl acetate-Skellysolve B); NMR peaks at 0.88, 3.67, 4.68-5.18,5.27-5.97, and 6.95-7.35 δ; infrared absorption bands at 2960, 2920,2850, 1740, 1610, 1590, 1490, 1440, 1365, 1260, 1240, 1195, 1155, 1060,785, and 705 cm⁻¹ ; and mass spectral peaks at 368, 350, 337, 326, 191,and 177.

Thereafter, following the procedures of Chart E, the product of Example21 is converted to the racemic glycol corresponding to formula LXXIwherein R₁ is methyl and thence todl-4,5,6-trinor-3,7-inter-m-phenylene-PGE₁, methyl ester, correspondingto formula LXXII, a useful compound.

Following the procedures of Examples 16-21 but using the opticallyactive form of starting material XXX (from Example 1), there areobtained the corresponding optically active intermediates and finalproducts.

I claim:
 1. A process for preparing an optically active compound of theformula ##STR127## or a racemic mixture of that compound and theenantiomer thereof, wherein R₁₉ is hydrogen or alkyl of one to 4 carbonatoms, inclusive; wherein R₅ and R₆ taken together are --CH₂ -C(CH₃)₂-CH₂ --; and wherein indicates attachment to the cyclopropane ring inendo or exo configuration, which comprises reacting an optically activecompound of the formula ##STR128## or a racemic mixture of that compoundand the enantiomer thereof, wherein , R₅ and R₆ are as defined above,with a compound of the formula ##STR129## wherein R₁₉ is as definedabove.
 2. An optically active compound of the formula ##STR130## or aracemic mixture of that compound and the enantiomer thereof, wherein R₁₉is hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein R₅ andR₆ taken together are --CH₂ -C(CH₃)₂ -CH₂ --; and wherein indicatesattachment to the cyclopropane ring in endo or exo configuration.